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Hou C, Zhong Y, Zhang L, Liu M, Yan F, Chen M, Wang Y, Xu P, Su M, Hu C, Di B. Estimating the prevalence of hypertension in 164 cities in China by wastewater-based epidemiology. JOURNAL OF HAZARDOUS MATERIALS 2023; 443:130147. [PMID: 36283217 DOI: 10.1016/j.jhazmat.2022.130147] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/12/2022] [Accepted: 10/06/2022] [Indexed: 06/16/2023]
Abstract
Hypertension is the most common chronic non-infectious disease and a severe problem for public health in China. There were 244.5 million people aged over 18 years in China who had hypertension in 2015, and hypertension-related death accounted for more than 25 % of all causes of death in China every year. To monitor the hypertension prevalence in near real-time, a wastewater-based epidemiology (WBE) approach by using metoprolol acid as a biomarker was conducted in 164 cities in China. LC-MS/MS was utilized to quantify metoprolol acid in sewage, and satisfactory method validation results were achieved. The average concentration of metoprolol acid in sewage was 943.1 ± 671.1 ng/L, and the back-calculated consumption of metoprolol based on metoprolol acid was 932.0 ± 390.5 mg/day/1000inh on average, ranging from 76.7 to 3275.7 mg/day/1000inh. The prevalence of metoprolol was estimated to be 0.83 % ± 0.35 %, and the estimated hypertension prevalence in the population aged over 15 years was ultimately assessed to be 28.56 % ± 10.44 % ranging from 14.28 % to 44.28 % and was consistent with the China Hypertension Survey result of 27.9 %. This research demonstrated that estimating hypertension prevalence by WBE with metoprolol acid as a biomarker is feasible in Chinese cities.
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Affiliation(s)
- Chenzhi Hou
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Yuling Zhong
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Lan Zhang
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Muyuan Liu
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Fang Yan
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Mengyi Chen
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Youmei Wang
- China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China; National Narcotics Laboratory, Drug Intelligence and Forensic Center of the Ministry of Public Security of the People's Republic of China, Beijing 100741, PR China; Key Laboratory of Drug Monitoring and Control, Ministry of Public Security, People's Republic of China, Beijing 100741, PR China
| | - Peng Xu
- China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China; National Narcotics Laboratory, Drug Intelligence and Forensic Center of the Ministry of Public Security of the People's Republic of China, Beijing 100741, PR China; Key Laboratory of Drug Monitoring and Control, Ministry of Public Security, People's Republic of China, Beijing 100741, PR China
| | - Mengxiang Su
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China
| | - Chi Hu
- China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China; Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 211198, PR China.
| | - Bin Di
- Department of Pharmacy, China Pharmaceutical University, No.24 Tongjiaxiang Road, Nanjing 210009, PR China; China National Narcotics Control Commission-China Pharmaceutical University Joint Laboratory on Key Technologies of Narcotics Control, Nanjing 210009, PR China.
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Zhao X, Zhang Z, Lu F, Xiong M, Jiang L, Tang K, Fu M, Wu Y, He B. Effects of CYP2C19 genetic polymorphisms on the cure rates of H. pylori in patients treated with the proton pump inhibitors: An updated meta-analysis. Front Pharmacol 2022; 13:938419. [PMID: 36278195 PMCID: PMC9582748 DOI: 10.3389/fphar.2022.938419] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022] Open
Abstract
Background: The cure rates of Helicobacter pylori (H. pylori) treatment using a proton pump inhibitor (PPI) are gradually decreasing due to antibiotic resistance, poor compliance, high gastric acidity, and cytochrome P450 2C19 (CYP2C19) polymorphism, and the effects of PPI depend on metabolic enzymes, cytochrome P450 enzymes. The aim of this meta-analysis was to determine whether CYP2C19 polymorphisms affect H. pylori cure rates in patients treated with different proton pump inhibitors (PPIs) according to stratified analysis. Materials and methods: The literature was searched with the key words “H. pylori” and “CYP2C19” in PubMed, CNKI, and Wanfang up to 31 May 2022, and the studies were limited to clinical observational or randomized controlled trials (RCTs). Finally, seven RCTs and 29 clinical observational studies met the inclusion criteria and were used for the meta-analysis via STATA version 16. Results: The cure rates were significantly different between genotypes of homozygous extensive metabolizers (EM) and poor metabolizers (PM) (OR = 0.58, 95% CI: 0.47–0.71) and between EM and heterozygous extensive metabolizers (IM) (OR = 0.71, 95% CI: 0.59–0.86), but not between IM and PM. Moreover, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with omeprazole (66.4% vs. 84.1%), lansoprazole (76.1% vs. 85.6%), but not rabeprazole, esomeprazole, or pantoprazole. In addition, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with a PPIs for 7 days (77.4% vs. 82.1%), but not 14 days (85.4% vs. 90.0%). Conclusion: Carriers of CYP2C19 loss-of-function variant alleles (IM and PM) exhibit a significantly greater cure rate of H. pylori than noncarriers (EM) regardless of other factors (84.7% vs. 79.2%). In addition, pantoprazole- and rabeprazole-based quadruple therapy for H. pylori treatment is less dependent on the CYP2C19 genotype and should be prioritized in Asian populations with H. pylori.
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Affiliation(s)
- Xianghong Zhao
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zhongqiu Zhang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Fang Lu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Mengqiu Xiong
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Liping Jiang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ke Tang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Min Fu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yu Wu
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bangshun He
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- H. pylori Research Key Laboratory, Nanjing Medical University, Nanjing, China
- *Correspondence: Bangshun He,
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Suetsugu K, Muraki S, Fukumoto J, Matsukane R, Mori Y, Hirota T, Miyamoto T, Egashira N, Akashi K, Ieiri I. Effects of Letermovir and/or Methylprednisolone Coadministration on Voriconazole Pharmacokinetics in Hematopoietic Stem Cell Transplantation: A Population Pharmacokinetic Study. Drugs R D 2021; 21:419-429. [PMID: 34655050 PMCID: PMC8602551 DOI: 10.1007/s40268-021-00365-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2021] [Indexed: 11/26/2022] Open
Abstract
Objective The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. Methods The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis–Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. Results The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1–5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. Conclusions The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00365-0.
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Affiliation(s)
- Kimitaka Suetsugu
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Shota Muraki
- Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Junshiro Fukumoto
- Department of Clinical Pharmacology and Biopharmaceutics, The Pharmaceutical College, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ryosuke Matsukane
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasuo Mori
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takeshi Hirota
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.,Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Toshihiro Miyamoto
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Nobuaki Egashira
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.,Department of Clinical Pharmacology and Biopharmaceutics, The Pharmaceutical College, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ichiro Ieiri
- Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. .,Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. .,Department of Clinical Pharmacology and Biopharmaceutics, The Pharmaceutical College, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
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Komahashi-Sasaki H, Yasui-Furukori N, Sasaki T, Shinozaki M, Hayashi Y, Kato K, Inoue Y, Tsuchimine S, Watanabe T, Sugawara N, Shimoda K. Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression. Ther Drug Monit 2021; 43:681-687. [PMID: 33306568 DOI: 10.1097/ftd.0000000000000854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 11/10/2020] [Indexed: 11/25/2022]
Abstract
BACKGROUND Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. METHODS This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. RESULTS Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). CONCLUSIONS This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.
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Affiliation(s)
- Hazuki Komahashi-Sasaki
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Norio Yasui-Furukori
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Taro Sasaki
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Masataka Shinozaki
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Yuki Hayashi
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Kazuko Kato
- Sakura La Mental Clinic, Utsunomiya, Tochigi; and
| | - Yoshimasa Inoue
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Shoko Tsuchimine
- National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan
| | - Takashi Watanabe
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Norio Sugawara
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
| | - Kazutaka Shimoda
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga
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Androshchuk V, Sabharwal N, St Noble V, Kelion A. Speeding up beta-blockade prior to coronary CT angiography: can we predict the dose of intravenous metoprolol required to achieve target heart rate in a given patient? Clin Radiol 2020; 76:236.e21-236.e25. [PMID: 33298312 DOI: 10.1016/j.crad.2020.09.026] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/30/2020] [Indexed: 10/22/2022]
Abstract
AIM To evaluate the use and safety of intravenous (IV) metoprolol in a cohort of patients undergoing coronary computed tomographic angiography (CCTA) at a university hospital, and in particular, to establish if the minimum dose required to achieve the target heart rate (HR) in a given patient can be predicted from the baseline HR. MATERIALS AND METHODS Patients undergoing CCTA at a tertiary centre between January 2015 and May 2018, with baseline HR ≥60 bpm requiring IV metoprolol, were identified retrospectively from the database. Patients with a contraindication to beta-blockade or an indication for CCTA other than coronary disease were excluded. HR at baseline and at the time of scanning were recorded, together with the total dose of IV metoprolol administered. RESULTS Of 625 patients identified, 330 (52.8%) achieved HR ≤60 with IV metoprolol. Patients who achieved target HR had lower baseline HR. They received a lower radiation exposure due to tight prospective gating and a lower tube voltage. The lower quartile dose of metoprolol administered was 5 mg for patients with baseline HR <65 beats per minute (bpm), but 10 mg for HR 65-74 bpm, and ≥20 mg for higher HRs. There were no cases of symptomatic bradycardia/hypotension. CONCLUSION Patients with a resting HR of ≥60 bpm can reasonably be given an initial minimum dose of 5-20 mg metoprolol IV before CCTA, with additional doses as required.
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Affiliation(s)
- V Androshchuk
- Department of Cardiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
| | - N Sabharwal
- Department of Cardiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - V St Noble
- Department of Cardiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - A Kelion
- Department of Cardiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Li Q, Huo H, Hu W, Sui Y, Tang Y. <p>Comparison of Bioavailability and Bioequivalence of Generic and Brand Name Formulations of Escitalopram Oxalate Tablets in Healthy Chinese Population Under Fasting and Fed Conditions</p>. Drug Des Devel Ther 2020; 14:5167-5177. [PMID: 33262577 PMCID: PMC7699441 DOI: 10.2147/dddt.s271970] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/28/2020] [Indexed: 11/23/2022] Open
Abstract
Purpose This study compared the bioequivalence of two formulations of escitalopram oxalate 20 mg tablets in terms of bioavailability and tolerability in healthy Chinese male and female subjects. Patients and Methods A randomized, single-blind, two-period, two-sequence crossover study was performed under fasting and fed conditions, with a 21-day washout period. In total, 24 healthy subjects (18 males and 6 females) were enrolled in the fasting test and the fed test, respectively. Blood samples were collected over 168 h post-dose in each period. The concentrations of escitalopram in plasma were determined by high-performance liquid chromatography coupled with a tandem mass spectrometry. Pharmacokinetic parameters used for bioequivalence assessment were determined from the drug concentration data using noncompartmental analysis. Results All subjects showed good medication compliance. The 90% confidence intervals (CIs) for the geometric mean ratios of AUC0-t, AUC0-∞, and Cmax were within the bioequivalence acceptance criteria (80.00% to 125.00%). Adverse events were recorded and no deaths or serious adverse events (SAEs) occurred. Conclusion Escitalopram oxalate 20 mg tablets produced in China were bioequivalent to the reference formulation (Lexapro®) in healthy Chinese male and female subjects under fasting and fed conditions.
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Affiliation(s)
- Qiuying Li
- Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang110840, People’s Republic of China
| | - Hua Huo
- Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang110840, People’s Republic of China
| | - Wenli Hu
- Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang110840, People’s Republic of China
| | - Yin Sui
- Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang110840, People’s Republic of China
| | - Yunbiao Tang
- Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang110840, People’s Republic of China
- Correspondence: Yunbiao Tang; Hua Huo Department of Drug Clinical Trial Management Agency, General Hospital of Northern Theater Command, Shenyang, People’s Republic of ChinaTel/Fax +86-24-28897206 Email ;
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Dhuya M, Pal MM, Hazra A, Chatterjee S, Gogtay N. Cytochrome P 450 2D6 polymorphism in eastern Indian population. Indian J Pharmacol 2020; 52:189-195. [PMID: 32874001 PMCID: PMC7446679 DOI: 10.4103/ijp.ijp_530_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 12/30/2019] [Accepted: 07/13/2020] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVES: Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes a quarter of prescription drugs. Polymorphisms of CYP2D6 gene and resultant phenotypic variations in metabolic activity have been described in various populations. We assessed the prevalence of CYP2D6 activity phenotypes, employing dextromethorphan (DXM) as probe drug in subjects with at least two parental generations residing in eastern India. MATERIALS AND METHODS: Unrelated healthy subjects took 60 mg DXM after fasting overnight. Blood samples were collected 3 h after dosing and plasma separated. DXM and its primary metabolite dextrorphan (DXT) were measured by liquid chromatography with tandem mass spectrometry. The DXM-to-DXT metabolic ratio (MR) was obtained for each subject. Histogram of MR values suggested bimodal distribution. A polynomial regression equation derived through probit analysis was solved to identify the antimode of the MR values. Subjects with log(MR) < antimode were extensive metabolizers (EMs). Log(MR) ≥ antimode indicated poor metabolizers (PMs). RESULTS: We evaluated the results from 97 participants. The median MR was 0.209 (interquartile range: 0.090–0.609), while the antimode for MR was 3.055. From these, it was inferred that three subjects were PMs, while the rest were EMs. CYP2D6 polymorphism prevalence is low (3.09%; 95% confidence interval: 0.35%–6.54%) in the population of eastern India and matches the prevalence in other zones of the country. CONCLUSIONS: Differences in CYP2D6 activity has treatment implications and may lead to adverse events or therapeutic failure. Phenotyping of subjects receiving CYP2D6 metabolized drugs may help clinicians personalize treatment and avert adverse drug-drug interactions. However, the frequency of the PM phenotype is low in India, and routinely phenotyping for CYP2D6 activity will not be cost-effective. We cannot recommend it at this stage.
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Affiliation(s)
- Monalisa Dhuya
- Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
| | - Murari Mohan Pal
- Department of Pharmaceutical Technology, Bioequivalence Study Centre, Jadavpur University, Kolkata, West Bengal, India
| | - Avijit Hazra
- Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
| | - Suparna Chatterjee
- Department of Pharmacology, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
| | - Nithya Gogtay
- Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai, Maharashtra, India
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Yang Q, Sun J, Li C, Zhang H, Xu W, Liu C, Zheng X. Comparative research on the metabolism of metoprolol by four CYP2D6 allelic variants in vitro with LC-MS/MS. J Pharm Biomed Anal 2019; 174:479-485. [PMID: 31228851 DOI: 10.1016/j.jpba.2019.06.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 04/28/2019] [Accepted: 06/10/2019] [Indexed: 11/18/2022]
Abstract
Specific study about the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on the metabolism of clinic drugs is of great significance for drug safety investigation. Here, the interaction between CYP2D6 variants (*1, *2, *10, *39) and metoprolol (MET) was intensively researched in vitro from the aspect of drug-enzyme kinetic study. To obtain quantitative data, α-hydroxymetoprolol (main metabolite of MET) was selected as an ideal analyte and an LC-MS/MS method was adopted for sample determination. Firstly, by selecting suitable internal standard and optimizing separation condition, the LC-MS/MS method was established and validated. Then, the drug-enzyme incubation system was optimized by two parameters: incubation time and amount of enzyme. Lastly, the interaction between CYP2D6 allelic variants and MET was characterized by Km, Vmax and CLint. As a result, four CYP2D6 enzymes displayed diverse Km or Vmax towards MET and the values of CLint showed a wide range from 8.91 to 100%. Relative to CYP2D6*1 (CLint*1 = 100%), CYP2D6*2 demonstrated the second high catalytic activity (CLint*2/*1 = 74.87%) while CYP2D6*39 (CLint*39/*1 = 29.65%) and CYP2D6*10 (CLint*10/*1 = 8.91%) showed minimal catalytic activity. This comprehensive in vitro data suggested the prominent influence of CYP2D6 polymorphisms on the metabolism of MET, which could offer valuable information for personalized administration of MET in clinic.
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Affiliation(s)
- Qingqing Yang
- Department of Pharmacology, Tianjin Medical University, Tianjin, 300070, China
| | - Jing Sun
- Department of Pharmacology, Tianjin Medical University, Tianjin, 300070, China
| | - Chuan Li
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China
| | - Haizhi Zhang
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.
| | - Weiren Xu
- Department of Pharmacology, Tianjin Medical University, Tianjin, 300070, China; Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.
| | - Changxiao Liu
- Tianjin Center for New Drug Evaluation and Research, State Key Laboratory of Drug Delivery Technology and Pharmaceutics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China
| | - Xuemin Zheng
- Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China
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9
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Lee DG, Lee HJ, Yan JL, Lin SSF, Aram JA. Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis. Mycoses 2019; 62:969-978. [PMID: 31355956 PMCID: PMC7003761 DOI: 10.1111/myc.12972] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 07/18/2019] [Accepted: 07/23/2019] [Indexed: 11/28/2022]
Abstract
This randomised, double‐blind, placebo‐controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non‐Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks’ treatment. The primary endpoint was 6‐ and 12‐week all‐cause mortality (Korean modified intent‐to‐treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non‐Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non‐Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was −6.4% in non‐Koreans. This reduction was more marked in Koreans (−22.4%). Week 12 difference in all‐cause mortality between combination and monotherapy was −17.7% (Koreans) and −20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5‐2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non‐Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non‐Koreans.
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Affiliation(s)
- Dong-Gun Lee
- Division of Infectious Diseases, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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10
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Hanauer Schaab E, Lanchote VL, Balthazar Nardotto GH, Marques Pereira MP, Dantas M, Paiva CE, Barbosa Coelho E. Effect of Lercanidipine on the Pharmacokinetics‐Pharmacodynamics of Carvedilol Enantiomers in Patients With Chronic Kidney Disease. J Clin Pharmacol 2019; 60:75-85. [DOI: 10.1002/jcph.1485] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/18/2019] [Indexed: 12/14/2022]
Affiliation(s)
- Estela Hanauer Schaab
- Faculdade de Ciências Farmacêuticas de Ribeirão PretoUniversidade de São Paulo Ribeirão Preto Brazil
| | - Vera Lucia Lanchote
- Faculdade de Ciências Farmacêuticas de Ribeirão PretoUniversidade de São Paulo Ribeirão Preto Brazil
| | | | | | - Márcio Dantas
- Faculdade de Medicina de Ribeirão PretoUniversidade de São Paulo Ribeirão Preto Brazil
| | - Carlos Eduardo Paiva
- Faculdade de Medicina de Ribeirão PretoUniversidade de São Paulo Ribeirão Preto Brazil
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11
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Zhong Z, Hou J, Li B, Zhang Q, Liu S, Li C, Liu Z, Yang M, Zhong W, Zhao P. Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China. Med Sci Monit 2017; 23:6186-6192. [PMID: 29288619 PMCID: PMC5757864 DOI: 10.12659/msm.905337] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Background Cytochrome P450 (CYP) 2C19 is an enzyme involved in the bioactivation of various important therapeutic drugs, from pro-drugs to an active inhibitor of platelet action. Variants in the CYP2C19 gene influence the pharmacokinetics and clinical response to antiplatelet drugs such as clopidogrel; however, there is no available data about the genetic variation of CYP2C19 in the Hakka population in China. Material/Methods A total of 6686 unrelated participants (ages 17–98 years) of self-reported Hakka ancestry admitted at an inpatient department in a hospital in southern China were successfully genotyped by the gene chip platform. Results The identified allele frequencies were CYP2C19*1 (64.33%), *2 (31.06%) and *3 (4.61%). The major prevalent genotype combinations were CYP2C19 *1/*1 (41.73%) and *1/*2 (39.65%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) (41.73%), intermediate metabolizers (IM) (45.21%), and poor metabolizers (PM) (13.06%). In the Hakka population, frequencies of the CYP2C19 *2 and *3 variants were observed to be close to those previously identified in Chinese and several other Asian populations. Conclusions Our study is the first to report on CYP2C19 polymorphisms in the Hakka population, and may help to optimize pharmacotherapy effectiveness by providing personalized medicine to this ethnic group in the near future.
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Affiliation(s)
- Zhixiong Zhong
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland).,Center for Precision Medicine, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Jingyuan Hou
- Center for Precision Medicine, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland).,Clinical Core Laboratory, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Bing Li
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Qifeng Zhang
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Sudong Liu
- Center for Precision Medicine, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland).,Clinical Core Laboratory, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Cunren Li
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Zhidong Liu
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Min Yang
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Wei Zhong
- Center for Cardiovascular Diseases, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
| | - Pingsen Zhao
- Center for Precision Medicine, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland).,Clinical Core Laboratory, Meizhou People's Hospital, Huangtang Hospital, Meizhou Hospital Affiliated to Sun Yat-sen University, Meizhou, Guangdong, China (mainland)
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12
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Nuki Y, Umeno J, Washio E, Maehata Y, Hirano A, Miyazaki M, Kobayashi H, Kitazono T, Matsumoto T, Esaki M. The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury. Aliment Pharmacol Ther 2017; 46:331-336. [PMID: 28481007 DOI: 10.1111/apt.14134] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 01/20/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. AIM To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. METHODS Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. RESULTS In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. CONCLUSIONS The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.
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Affiliation(s)
- Y Nuki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - J Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - E Washio
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Y Maehata
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - A Hirano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - M Miyazaki
- Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan
| | - H Kobayashi
- Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan
| | - T Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - T Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - M Esaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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13
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Pharmacodynamic and cytogenetic evaluation in CYP2C19*2 and CYP2C19*3 allelomorphism in South Indian population with clopidogrel therapy. Int J Cardiol 2017; 229:113-118. [DOI: 10.1016/j.ijcard.2016.11.217] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 11/07/2016] [Indexed: 01/10/2023]
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14
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Motoi Y, Watanabe K, Honma H, Tadano Y, Hashimoto H, Kubota T. Digital PCR for determination of cytochrome P450 2D6 and sulfotransferase 1A1 gene copy number variations. Drug Discov Ther 2017; 11:336-341. [DOI: 10.5582/ddt.2017.01057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Yutaro Motoi
- Niigata University of Pharmacy and Applied Life Sciences
| | | | - Hiroyuki Honma
- Niigata University of Pharmacy and Applied Life Sciences
| | - Yousuke Tadano
- Niigata University of Pharmacy and Applied Life Sciences
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15
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Wilairatana P, Kyle DE, Looareesuwan S, Chinwongprom K, Amradee S, White NJ, Watkins WM. Poor efficacy of antimalarial biguanide-dapsone combinations in the treatment of acute, uncomplicated, falciparum malaria in Thailand. ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY 2016. [DOI: 10.1080/00034983.1997.11813121] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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16
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Mochizuki E, Furuhashi K, Fujisawa T, Enomoto N, Inui N, Nakamura Y, Kono M, Hamada E, Maekawa M, Suda T. A case of treatment with voriconazole for chronic progressive pulmonary aspergillosis in a patient receiving tacrolimus for dermatomyositis-associated interstitial lung disease. Respir Med Case Rep 2016; 16:163-5. [PMID: 26744690 PMCID: PMC4681998 DOI: 10.1016/j.rmcr.2015.10.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 10/25/2015] [Accepted: 10/29/2015] [Indexed: 11/28/2022] Open
Abstract
We report a successful treatment with voriconazole (VRCZ) for chronic progressive pulmonary aspergillosis (CPPA) in a patient with dermatomyositis-associated interstitial lung disease (DM-ILD) treated with tacrolimus. A 73-year-old man with DM-ILD, treated with tacrolimus and prednisolone, complained of productive cough and his chest X-ray showed infiltration in the left upper lung field. We diagnosed CPPA and added VRCZ. Although we reduced the dose of tacrolimus for drug interaction, serum VRCZ level increased after the treatment. The patient was found to have cytochrome P450 (CYP) 2C19 *2/*2, a genetic polymorphism in poor metabolizers of VRCZ. We adjusted the doses of both drugs and treated him successfully. We recommend performing individual therapeutic drug monitoring (TDM) in CYP-mediated drug interactions and considering the effect of CYP polymorphisms.
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Affiliation(s)
- Eisuke Mochizuki
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kazuki Furuhashi
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomoyuki Fujisawa
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Noriyuki Enomoto
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naoki Inui
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yutaro Nakamura
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Kono
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Etsuko Hamada
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takafumi Suda
- Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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17
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Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations. THE PHARMACOGENOMICS JOURNAL 2015; 16:113-23. [PMID: 26503820 DOI: 10.1038/tpj.2015.70] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/15/2015] [Accepted: 08/19/2015] [Indexed: 02/08/2023]
Abstract
The present study evaluates the worldwide frequency distribution of CYP2C19 alleles and CYP2C19 metabolic phenotypes ('predicted' from genotypes and 'measured' with a probe drug) among healthy volunteers from different ethnic groups and geographic regions, as well as the relationship between the 'predicted' and 'measured' CYP2C19 metabolic phenotypes. A total of 52 181 healthy volunteers were studied within 138 selected original research papers. CYP2C19*17 was 42- and 24-fold more frequent in Mediterranean-South Europeans and Middle Easterns than in East Asians (P<0.001, in both cases). Contrarily, CYP2C19*2 and CYP2C19*3 alleles were more frequent in East Asians (30.26% and 6.89%, respectively), and even a twofold higher frequency of these alleles was found in Native populations from Oceania (61.30% and 14.42%, respectively; P<0.001, in all cases), which may be a consequence of genetic drift process in the Pacific Islands. Regarding CYP2C19 metabolic phenotype, poor metabolizers (PMs) were more frequent among Asians than in Europeans, contrarily to the phenomenon reported for CYP2D6. A correlation has been found between the frequencies of CYP2C19 poor metabolism 'predicted' from CYP2C19 genotypes (gPMs) and the poor metabolic phenotype 'measured' with a probe drug (mPMs) when subjects are either classified by ethnicity (r=0.94, P<0.001) or geographic region (r=0.99, P=0.002). Nevertheless, further research is needed in African and Asian populations, which are under-represented, and additional CYP2C19 variants and the 'measured' phenotype should be studied.
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18
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Kuo CH, Lu CY, Shih HY, Liu CJ, Wu MC, Hu HM, Hsu WH, Yu FJ, Wu DC, Kuo FC. CYP2C19 polymorphism influences Helicobacter pylori eradication. World J Gastroenterol 2014; 20:16029-16036. [PMID: 25473155 PMCID: PMC4239489 DOI: 10.3748/wjg.v20.i43.16029] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 07/04/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.
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19
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Furuta K, Kohata Y, Fujiwara Y, Sugimoto M, Uotani T, Yamade M, Sahara S, Ichikawa H, Furuta T, Nio K, Iwakiri R, Inamori M, Kawamura O, Kusano M, Kato M, Kawami N, Iwakiri K, Takeuchi T, Higuchi K, Aimi M, Naora K, Fujimoto K, Arakawa T, Kinoshita Y. Intra-gastric pH following single oral administrations of rabeprazole and esomeprazole: double-blind cross-over comparison. J Clin Biochem Nutr 2014; 55:178-183. [PMID: 25411523 PMCID: PMC4227829 DOI: 10.3164/jcbn.14-41] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 05/14/2014] [Indexed: 01/25/2023] Open
Abstract
Comparisons between the acid inhibitory effects of rabeprazole and esomeprazole after single oral administration with standard doses have not been previously presented. We examined intra-gastric pH after oral administrations of these two proton pump inhibitors using 24-h pH monitoring. Fifty-four normal volunteers not infected by Helicobacter pylori were investigated. Using a cross-over design, we administered 10 mg of rabeprazole or 20 mg of esomeprazole in 27 at 30 min after supper and in the remaining 27 subjects at 15 min before supper, and performed 24-h pH monitoring. Intra-gastric pH data were nearly identical when the proton pump inhibitors were taken after meals. Even if the data were compared in different CYP2C19 genotypes, rabeprazole and esomeprazole did not show the difference. In poor metabolizer, both of the drugs showed stronger acid inhibition. When taken before meals, intra-gastric pH after esomeprazole administration was slightly but not significantly higher than that observed after rabeprazole administration not only in daytime but also in nighttime period. In conclusion, rabeprazole and esomeprazole were similarly effective when administered after a meal.
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Affiliation(s)
- Kenji Furuta
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Yukie Kohata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-5-7 Asahi-cho, Abeno-ku, Osaka 545-8586, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-5-7 Asahi-cho, Abeno-ku, Osaka 545-8586, Japan
| | - Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan
| | - Kenta Nio
- Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Ryuichi Iwakiri
- Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Masahiko Inamori
- Gastroenterology Division, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
| | - Osamu Kawamura
- Department of Gastroenterology, Gunma University Hospital, 3-39-15 Showa-cho, Maebashi, Gunma 371-8511, Japan
| | - Motoyasu Kusano
- Department of Endoscopy and Endoscopic Surgery, Gunma University Hospital, 3-39-15 Showa-cho, Maebashi, Gunma 371-8511, Japan
| | - Mototsugu Kato
- Division of Endoscopy, Hokkaido University Hospital, Nishi 5-chome, Kita 14-jou, Kita-ku, Sapporo, Hokkaido 060-8648, Japan
| | - Noriyuki Kawami
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
| | - Toshihisa Takeuchi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, Osaka 569-8686, Japan
| | - Kazuhide Higuchi
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki, Osaka 569-8686, Japan
| | - Masahito Aimi
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kohji Naora
- Department of Pharmacy, Shimane University Hospital, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
| | - Kazuma Fujimoto
- Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan
| | - Tetsuo Arakawa
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-5-7 Asahi-cho, Abeno-ku, Osaka 545-8586, Japan
| | - Yoshikazu Kinoshita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, 89-1 Enya-cho, Izumo, Shimane 693-8501, Japan
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Tabari RG, Marjani A, Ataby OA, Mansourian AR, Samai NM. Genetic Polymorphism of Cytochrome p450 (2C19) Enzyme in Iranian Turkman Ethnic Group. Oman Med J 2013; 28:237-44. [PMID: 23904915 DOI: 10.5001/omj.2013.69] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Accepted: 05/28/2013] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Different findings indicate that CYP2C plays a clinical role in determining interindividual and interethnic differences in drug effectiveness. The ethnic differences in the frequency of CYP2C19 mutant alleles continue to be a significant study topic. The aim of the present study was to assess the frequency of allelic variants of CYP2C19 in Turkman ethnic groups and compare them with the frequencies in other ethnic populations. METHODS The study group included 140 unrelated healthy ethnic Turkman subject referred to the Health Center. Genotyping of CYP2C19 alleles (CYP2C19*1, CYP2C19*2, and CYP2C19*3 alleles) was carried out by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism technique. RESULTS The allele frequency of CYP2C19*1, CYP2C19*2 and CYP2C19*3 were 56.43%, 23.57% and 20%, respectively. The result also showed that 39.7% of subjects expressed the CYP2C19*1/*1 genotype. While 42.1%, 9.3%, 9.3% and 1.4% expressed CYP2C19*1/*2, CYP2C19*1/*3, CYP2C19*2/*2 and CYP2C19*3/*3 genotypes, respectively. The genotype CYP2C19*2/*3 was not expressed in this study population. The findings suggested that 10% of subjects were poor metabolizers by expressing CYP2C19*2/*2 and CYP2C19*3/*3 genotypes. Fifty one percent of subjects were intermediate metabolizers having CYP2C19*1/*2, CYP2C19*2/*3 and CYP2C19*1/*3 genotypes and 37.86% were found to be extensive metabolizers expressing CYP2C19*1/*1 genotype. The frequency of intermediate metabolizers genotype was high (51%) in Turkman ethnic groups. CONCLUSION This study showed that the determined allelic variants of CYP2C19 (CYP2C19*2 and CYP2C19*3 mutations) in Turkman ethnic group are comparable to other populations. These findings could be useful for the clinicians in different country to determine optimal dosage and effectiveness of drugs metabolized by this polymorphic enzyme.
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Affiliation(s)
- Robabeh Ghiyas Tabari
- Department of Biochemistry and Biophysics, Metabolic Disorders Research Center, Gorgan Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Golestan province, Iran
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Neves DV, Lanchote VL, de Souza L, Hayashida M, Nogueira MS, de Moraes NV, Cesarino EJ. Metoprolol oxidation polymorphism in Brazilian elderly cardiac patients. J Pharm Pharmacol 2013; 65:1347-53. [DOI: 10.1111/jphp.12109] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Accepted: 06/15/2013] [Indexed: 11/29/2022]
Abstract
Abstract
Objectives
The purpose of this study was to phenotype the CYP2D6 in elderly with heart disease classified as extensive metabolizer or poor metabolizers (PM) of metoprolol, develop and validate the method of analysis of metoprolol tartrate and its metabolite in urine using HPLC, and identify potential correlations between anthropometric factors with metabolic ratios of metoprolol/α-OH metoprolol in urine.
Methods
The sample was composed of 130 elderly individuals with a previously identified type of heart condition, with normal renal and hepatic functions. The urine of all the patients were collected 0–8 h after the administration of a pill of 100 mg of metoprolol to determine concentrations of metoprolol and α-hydroxymetoprolol. Those patients presenting a metabolic ratio greater than 12.6 were phenotyped as PM.
Key findings
The median age of patients was 71.0 years, with a minimum of 60 and maximum of 93 years old. Three patients (2.3%) were phenotyped as PM of metoprolol different from the rate (7–10%) of PM existing in the Caucasian population.
Conclusions
Most of the studied individuals were women, and the proportion of elderly with heart disease classified as PM was smaller than what is usually found among Caucasian populations.
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Affiliation(s)
- Daniel Valente Neves
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Vera Lucia Lanchote
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Luiz de Souza
- School of Medicine of Ribeirão Preto, Department of Child Care and Pediatrics, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Miyeko Hayashida
- College of Nursing, Department of General and Specialized Nursing, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Maria Sueli Nogueira
- College of Nursing, Department of General and Specialized Nursing, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Natália Valadares de Moraes
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Evandro José Cesarino
- School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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Yuan Y, Yang L, Shi M, Lu D, Lou H, Chen YPP, Jin L, Xu S. Identification of well-differentiated gene expressions between Han Chinese and Japanese using genome-wide microarray data analysis. J Med Genet 2013; 50:534-42. [DOI: 10.1136/jmedgenet-2012-101501] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Orengo-Mercado C, Nieves B, López L, Vallés-Ortiz N, Renta JY, Santiago-Borrero PJ, Cadilla CL, Duconge J. Frequencies of Functional Polymorphisms in Three Pharmacokinetic Genes of Clinical Interest within the Admixed Puerto Rican Population. JOURNAL OF PHARMACOGENOMICS & PHARMACOPROTEOMICS 2013; 4:1000113. [PMID: 24040574 PMCID: PMC3769800 DOI: 10.4172/2153-0645.1000113] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
OBJECTIVE This cross-sectional study was aimed at determining the allele frequencies for the CYP2C19*2, CYP2C19*3, CYP2D6*10 and PON1 (rs662) polymorphisms in the Puerto Rican population. The CYP2C19, CYP2D6 and PON1 genes are known to be associated with functional changes in drug metabolism and activation. Individuals carrying the aforementioned polymorphisms are at a higher risk of suffering from drug-induced adverse events and/ or unresponsiveness from a variety of drugs that includes antidepressants, atypical antipsychotics and antiplatelet compounds. Information on the frequency of these polymorphisms is more commonly found on homogeneous populations, but is scarce in highly heterogeneous populations like Hispanics, as in the case of Puerto Ricans. METHOD Genotyping was carried out in 100 genomic DNA samples from dried blood spots supplied by the Puerto Rican Newborn Screening program using Taqman® Genotyping Assays. RESULTS The Minor Allele Frequencies (MAF) obtained were 9% for CYP2C19*2 and CYP2D6*10, 50% for PON1 (rs662), while the CYP2C19*3 variant was not detected in our study. Furthermore, Hardy Weinberg equilibrium analysis was assessed as well as a comparison between Puerto Rico and other reference populations using a Z-test for proportions. CONCLUSION The observed allele and genotype frequencies on these relevant pharmacogenes in Puerto Ricans were more closely related to those early reported in two other reference populations of Americans (Mexicans and Colombians).
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Affiliation(s)
- Carmelo Orengo-Mercado
- Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Bianca Nieves
- Faculty of Natural Sciences, Rio Piedras Campus, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Lizbeth López
- Faculty of Natural Sciences, Rio Piedras Campus, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Nabila Vallés-Ortiz
- School of Natural Sciences, Bayamón Campus, University of Puerto Rico, Bayamón, Puerto Rico, USA
| | - Jessicca Y. Renta
- Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Pedro J. Santiago-Borrero
- Puerto Rico Newborn Screening Program, Department of Pediatrics, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Carmen L. Cadilla
- Department of Biochemistry, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
| | - Jorge Duconge
- School of Pharmacy, Department of Pharmaceutical Sciences, University of Puerto Rico, San Juan, Puerto Rico, USA
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Lehmann DF, Medicis JJ, Franklin PD. Polymorphisms and the Pocketbook: The Cost-Effectiveness of Cytochrome P450 2C19 Genotyping in the Eradication ofHelicobacter pyloriInfection Associated with Duodenal Ulcer. J Clin Pharmacol 2013; 43:1316-23. [PMID: 14615467 DOI: 10.1177/0091270003259389] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The clinical outcome of duodenal ulcer treated with proton pump inhibitor (PPI)-based, anti-Helicobacter pylori (H.p.) regimens varies according to cytochrome P450 2C19 (CYP2C19) genotype. CYP2C19 genotypes differ markedly in peoples of Pacific Rim descent compared with another ethnicity. The authors sought to determine the specific impact that these factors have on the cost-effectiveness of duodenal ulcer management. Their model consisted of two patient cohorts with Helicobacter pylori and duodenal ulcer, trichotomized into CYP2C19 homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs), altering the anti-H.p. regimen in the genotyped cohort only. The authors took the perspective of a third-party payer, and the denominator was ulcer episode prevented. In the reference case, the use of CYP2C19 genotyping prior to initiating anti-H.p. therapy was dominant (costs were saved with each ulcer episode prevented) in all geographic regions of the United States. The subsequent break-even analysis showed a range of 89.20 dollars to 118.96 dollars--from Hawaii to the Midwest, respectively--required to eliminate the cost-savings from each genotype test performed. Using probabilities most unfavorable to genotyping, the variation of peoples with Pacific Rim origins from 0% to 100% altered the cost-effectiveness from 495 dollars to 2125 dollars per ulcer event prevented, respectively. The results suggest that treatment decisions for H.p. infection that are based on a patient's CYP2C19 genotype decreases expenses for health plans implementing testing. This analysis provides an economic basis to support recent calls to expand this technology into routine clinical care to prevent toxicity of narrow therapeutic index drugs.
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Affiliation(s)
- David F Lehmann
- SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA
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Pharmacokinetics and Bioavailability Comparison of Generic and Branded Citalopram 20 mg Tablets. Clin Drug Investig 2012. [DOI: 10.1007/s40261-012-0010-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Setiabudy R, Chiba K, Kusaka M, Ishizaki T. Caution in the use of a 100 mg dose of racemic mephenytoin for phenotyping southeastern Oriental subjects [letter]. Br J Clin Pharmacol 2012. [DOI: 10.1111/j.1365-2125.1992.tb04099.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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Yamane K, Kato Y, Tazaki J, Tada T, Makiyama T, Imai M, Jinnai T, Ikeda T, Shirakawa R, Kimura T, Horiuchi H. Effects of PPIs and an H2 blocker on the antiplatelet function of clopidogrel in Japanese patients under dual antiplatelet therapy. J Atheroscler Thromb 2012; 19:559-69. [PMID: 22472213 DOI: 10.5551/jat.11601] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
AIM Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is essential after percutaneous coronary intervention (PCI). Clopidogrel is a prodrug and changed into active metabolite by cytochrome p450 enzymes (CYPs), especially CYP2C19. Proton pump inhibitors (PPIs) are used for the prevention of aspirin-induced gastrointestinal bleeding. PPIs are also metabolized by CYP2C19, although the degree of its contribution is dependent on the kind of PPI. Omeprazole, a PPI, has been reported to weaken the antiplatelet effects of clopidogrel. Famotidine, a histamine receptor type 2 (H2) blocker, could also be an alternative to PPIs. The aim of this study was to evaluate the effects of PPIs and an H2 blocker on the antiplatelet function of clopidogrel. METHODS Patients receiving DAPT due to prior PCI, who took either omeprazole or rabeprazole, were enrolled (n=25). The initial PPI was changed to the other PPI as a crossover study. In another study, patients undergoing DAPT without taking PPIs or H2 blockers were enrolled (n=30) and famotidine was added. RESULTS Platelet aggregability when taking omeprazole was higher than when taking rabeprazole, evaluated by an optical aggregometer using collagen as a stimulus (p=0.0051) and by the VerifyNow P2Y12 assay (p=0.0060). Platelet aggregability when taking rabeprazole was comparable to that in control patients (n=15). Concomitant use of famotidine had no effect. CONCLUSION Omeprazole significantly reduced the antiplatelet effect of clopidogrel and this effect on clopidogrel was stronger than that of rabeprazole. Concomitant use of famotidine had no effect on the antiplatelet effect of clopidogrel.
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Affiliation(s)
- Keiichiro Yamane
- Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Azuma J, Hasunuma T, Kubo M, Miyatake M, Koue T, Higashi K, Fujiwara T, Kitahara S, Katano T, Hara S. The relationship between clinical pharmacokinetics of aripiprazole and CYP2D6 genetic polymorphism: effects of CYP enzyme inhibition by coadministration of paroxetine or fluvoxamine. Eur J Clin Pharmacol 2011; 68:29-37. [PMID: 21739267 PMCID: PMC3249179 DOI: 10.1007/s00228-011-1094-4] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2011] [Accepted: 06/15/2011] [Indexed: 11/30/2022]
Abstract
Purpose To investigate the effects of coadministration of paroxetine or fluvoxamine on the pharmacokinetics of aripiprazole in healthy adult Japanese with different CYP2D6 genotypes. Methods Fourteen CYP2D6 extensive metabolizer (EM) and 14 CYP2D6 intermediate metabolizer (IM) subjects were coadministered a single oral dose of aripiprazole 3 mg after steady-state plasma concentrations of the SSRIs paroxetine (20 mg/day) or fluvoxamine (100 mg/day) were reached by repeated oral doses for 6–7 days. The pharmacokinetics of aripiprazole with and without coadministration of SSRIs were compared according to CYP2D6 genotypes. Results Coadministration of paroxetine, a potent CYP2D6 inhibitor, decreased systemic clearance (CL/F) of aripiprazole by 58 and 23% in CYP2D6 EMs and IMs, respectively, demonstrating that the percentage inhibition of CYP2D6 activity by coadministration of paroxetine was apparently greater in CYP2D6 EMs than in IMs. Coadministration of fluvoxamine, a less potent CYP3A4 inhibitor, decreased the CL/F of aripiprazole by 39% in CYP2D6 EMs and 40% in IMs, indicating the same inhibitory effect on CYP enzymes, regardless of the CYP2D6 genotype. Percent contribution of CYP2D6 to total CL/F (CYP2D6 plus CYP3A4) of aripiprazole estimated as a reduced percentage of CL/F by CYP enzyme inhibition was 62% for CYP2D6 EMs and 24% for IMs in paroxetine coadministration, and 40% for CYP2D6 EMs and 18% for IMs in fluvoxamine coadministration. Conclusions There were marked differences in the degree of influence of paroxetine coadministration on the pharmacokinetics of aripiprazole between CYP2D6 EMs and IMs, but no apparent differences were found between two CYP2D6 genotypes in fluvoxamine coadministration. Aripiprazole can be used safely in combination with SSRIs that have a CYP enzyme-inhibitory action.
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Affiliation(s)
- Junichi Azuma
- Clinical Pharmacology and Pharmacogenomics, Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, 1-3-6, Minatojima, Chuo-ku, Kobe, 650-8530, Japan.
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Tsai MH, Lin KM, Hsiao MC, Shen WW, Lu ML, Tang HS, Fang CK, Wu CS, Lu SC, Liu SC, Chen CY, Liu YL. Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response. Pharmacogenomics 2010; 11:537-46. [PMID: 20350136 DOI: 10.2217/pgs.09.168] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response. MATERIALS & METHODS A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers. RESULTS The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p < 0.05). The allele frequencies in CYP3A4*18 and CYP2C19*17 were too low to permit further subgroup analyses. CONCLUSION Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.
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Affiliation(s)
- Ming-Hsien Tsai
- Division of Mental Health & Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan
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Lee JH, Jung HY, Choi KD, Song HJ, Lee GH, Kim JH. The Influence of CYP2C19 Polymorphism on Eradication of Helicobacter pylori: A Prospective Randomized Study of Lansoprazole and Rabeprazole. Gut Liver 2010; 4:201-6. [PMID: 20559522 DOI: 10.5009/gnl.2010.4.2.201] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 01/19/2010] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS The CYP2C19 polymorphism plays an important role in the metabolism of various proton-pump inhibitors. Several trials have produced conflicting data on eradication rates of Helicobacter pylori (H. pylori) among CYP2C19 genotypes. We investigated whether the CYP2C19 genotype affects the eradication rate of H. pylori by direct comparing the effects of lansoprazole- and rabeprazole-based triple therapies. METHODS A total of 492 patients infected with H. pylori was randomly treated with either 30 mg of lansoprazole or 20 mg of rabeprazole plus 500 mg of clarithromycin and 1,000 mg of amoxicillin twice daily for 1 week. CYP2C19 genotype status was determined by a PCR-restriction-fragment-length polymorphism method. After 7 to 8 weeks, H. pylori status was evaluated by a C(13)-urea breath test. RESULTS Four hundred and sixty-three patients were analyzed, and the eradication rate was 75.2% in a per-protocol analysis. Eradication rates for the lansoprazole regimen (n=234) were 73.8%, 80.7%, and 85.4% in the homozygous extensive (HomEM), heterozygous extensive (HetEM), and poor metabolizers (PM) groups, respectively (p=0.303). In the case of the rabeprazole regimen (n=229), the eradication rates were 68.6%, 73.0%, and 71.9% in the HomEM, HetEM, and PM groups, respectively (p=0.795). CONCLUSIONS The efficacies of triple therapies that include lansoprazole or rabeprazole are not affected by CYP2C19 genetic polymorphisms.
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Affiliation(s)
- Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Ramsjö M, Aklillu E, Bohman L, Ingelman-Sundberg M, Roh HK, Bertilsson L. CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking. Eur J Clin Pharmacol 2010; 66:871-7. [DOI: 10.1007/s00228-010-0835-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2010] [Accepted: 05/02/2010] [Indexed: 01/08/2023]
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Yang JC, Lin CJ. CYP2C19 genotypes in the pharmacokinetics/pharmacodynamics of proton pump inhibitor-based therapy of Helicobacter pylori infection. Expert Opin Drug Metab Toxicol 2010; 6:29-41. [PMID: 19968574 DOI: 10.1517/17425250903386251] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Proton pump inhibitors (PPIs) are potent gastric acid inhibitors. Therapies with a PPI and antibiotics are used to cure Helicobacter pylori (H. pylori) infection, which is closely related to many gastrointestinal diseases. Most PPIs are mainly metabolized by cytochrome 2C19 (CYP2C19). The genetic polymorphisms of CYP2C19 may lead to the differences in pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of PPIs. AREAS COVERED IN THIS REVIEW The roles of PPIs on the eradication of H. pylori are summarized. The impact f CYP2C19 polymorphism on the PK and PD of PPIs is addressed and related to the present status of therapy for H. pylori infection. The opinions on the strategy of PPIs-based therapies of H. pylori infection are provided. WHAT THE READER WILL GAIN Update the factors that may influence the PPIs-based therapies of H. pylori infection. TAKE HOME MESSAGE The eradication rates of H. pylori infection are significantly different between patients who are CYP2C19 extensive metabolizers and poor metabolizers, partly because of the differences in the PK and PD of PPIs. Nonetheless, the differences can be improved by adjusting the regimens of PPIs and using antibiotics that have less H. pylori-resistance.
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Affiliation(s)
- Jyh-Chin Yang
- National Taiwan University, Hospital and College of Medicine, Department of Internal Medicine, Taipei, Taiwan
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Affiliation(s)
- Shu-Feng Zhou
- Discipline of Chinese Medicine, School of Health Sciences, RMIT University, Victoria, Australia.
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Nonen S, Azuma J. [Genetic polymorphism of CYP-450 in drug development]. Nihon Yakurigaku Zasshi 2009; 134:212-5. [PMID: 19828926 DOI: 10.1254/fpj.134.212] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Inoue S, Howgate EM, Rowland-Yeo K, Shimada T, Yamazaki H, Tucker GT, Rostami-Hodjegan A. Prediction ofin vivodrug clearance fromin vitrodata. II: Potential inter-ethnic differences. Xenobiotica 2008; 36:499-513. [PMID: 16865818 DOI: 10.1080/00498250600683262] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in vitro metabolism data were available and clearance values had been reported both in Caucasians and Japanese). Values of relevant biological variables were obtained from the literature, and clearance predictions were made using the Simcyp Population-Based ADME Simulator. The ratios of observed oral clearance (CLp.o.) values in Caucasians compared with Japanese ranged from 0.6 to 2.8 (integrating data from 82 sources). The CLp.o. values for alprazolam, caffeine and zolpidem were not statistically different between Caucasian and Japanese (p>0.05), whereas those for chorzoxazone, cyclosporine, omeprazole, tolbutamide and triazolam were higher in Caucasians (p<0.05), and those for midazolam, sildenafil and S-warfarin were higher in Japanese (p<0.05). CLp.o. values, predicted from in vitro data, were within 3-fold of observed in vivo values for seven of the 11 drugs in Japanese. Values for the predicted ratios ranged from 1.6 to 4.9. The predicted ratios were not significantly different from observed ratios for cyclosporine, omeprazole, tolbutamide and triazolam. Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables. With such information, in silico predictions might be used with more confidence to decrease the need for repeating pharmacokinetic studies in different ethnic groups.
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Affiliation(s)
- S Inoue
- Academic Unit of Clinical Pharmacology, Division of Clinical Sciences (South), University of Sheffield Royal Hallamshire Hospital, Sheffield, UK
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Lim HS, Ju Lee H, Seok Lee K, Sook Lee E, Jang IJ, Ro J. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer. J Clin Oncol 2007; 25:3837-45. [PMID: 17761971 DOI: 10.1200/jco.2007.11.4850] [Citation(s) in RCA: 190] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The CYP3A and CYP2D6 enzymes play a major role in converting tamoxifen to its active metabolites. CYP3A is a highly inducible enzyme, regulated mainly by pregnane X receptor (PXR). This study assessed the association between genetic polymorphisms of CYP2D6 and PXR, and tamoxifen pharmacokinetics (PK) and clinical outcomes in patients with breast cancer. PATIENTS AND METHODS Plasma concentrations of tamoxifen and its metabolites were measured. Common alleles of CYP2D6 and PXR were identified in 202 patients treated with tamoxifen 20 mg daily for more than 8 weeks. Twelve of the 202 patients and an additional nine patients with metastatic breast cancer receiving tamoxifen were assessed for clinical outcome in correlation with genotypes. RESULTS Patients carrying CYP2D6*10/*10 (n = 49) demonstrated significantly lower steady-state plasma concentrations of 4-hydroxy-N-desmethyltamoxifen and 4-hydroxytamoxifen than did those with other genotypes (n = 153; 4-hydroxy-N-desmethyltamoxifen: 7.9 v 18.9 ng/mL, P < .0001; 4-hydroxytamoxifen: 1.5 v 2.6 ng/mL, P < .0001), whereas no difference by PXR genotypes was found. CYP2D6*10/*10 was significantly more frequent among nonresponders with MBC (100% v 50%, P = .0186). In Cox proportional hazard analysis, CYP2D6 genotype and number of disease sites were significant factors affecting time to progression (TTP). The median TTP for patients receiving tamoxifen was shorter in those carrying CYP2D6*10/*10 than for others (5.0 v 21.8 months, P = .0032) CONCLUSION CYP2D6*10/*10 is associated with lower steady-state plasma concentrations of active tamoxifen metabolites, which could possibly influence the clinical outcome by tamoxifen in Asian breast cancer patients.
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Affiliation(s)
- Hyeong-Seok Lim
- Research Institute and Hospital, National Cancer Center, Madu1-dong, Ilsan-gu, Goyang-si, Gyeonggi-do, Republic of Korea
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Shen H, He MM, Liu H, Wrighton SA, Wang L, Guo B, Li C. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 2007; 35:1292-300. [PMID: 17470523 DOI: 10.1124/dmd.107.015354] [Citation(s) in RCA: 127] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene are a major cause of pharmacokinetic variability in human. Although the poor metabolizer phenotype is known to be caused by two null alleles leading to absence of functional CYP2D6 protein, the large variability among individuals with functional alleles remains mostly unexplained. Thus, the goal of this study was to examine the intrinsic enzymatic differences that exist among the several active CYP2D6 allelic variants. The relative catalytic activities (enzyme kinetics) of three functionally active human CYP2D6 allelic variants, CYP2D6.1, CYP2D6.10, and CYP2D6.17, were systematically investigated for their ability to metabolize a structurally diverse set of clinically important CYP2D6-metabolized drugs [atomoxetine, bufuralol, codeine, debrisoquine, dextromethorphan, (S)-fluoxetine, nortriptyline, and tramadol] and the effects of various CYP2D6-inhibitors [cocaine, (S)-fluoxetine, (S)-norfluoxetine, imipramine, quinidine, and thioridazine] on these three variants. The most significant difference observed was a consistent but substrate-dependent decease in the catalytic efficiencies of cDNA-expressed CYP2D6.10 and CYP2D6.17 compared with CYP2D6.1, yielding 1.32 to 27.9 and 7.33 to 80.4% of the efficiency of CYP2D6.1, respectively. The most important finding from this study is that there are mixed effects on the functionally reduced allelic variants in enzyme-substrate affinity or enzyme-inhibitor affinity, which is lower, higher, or comparable to that for CYP2D6.1. Considering the rather high frequencies of CYP2D6*10 and CYP2D6*17 alleles for Asians and African Americans, respectively, these data provide further insight into ethnic differences in CYP2D6-mediated drug metabolism. However, as with all in vitro to in vivo extrapolations, caution should be applied to the clinical consequences.
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Affiliation(s)
- Hongwu Shen
- Shanghai Institute of Materia Medica, Graduate School, Chinese Academy of Sciences, Zhangjiang Hi-Tech Park, Shanghai, China
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Li ZS, Zhan XB, Xu GM, Cheng NN, Liao Z. Effect of esomeprazole and rabeprazole on intragastric pH in healthy Chinese: an open, randomized crossover trial. J Gastroenterol Hepatol 2007; 22:815-20. [PMID: 17565634 DOI: 10.1111/j.1440-1746.2006.04709.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Esomeprazole is the S-isomer of omeprazole, with a stronger acid suppressive effect than omeprazole. This open, randomized crossover study was designed to evaluate the effect of esomeprazole and another proton-pump inhibitor, rabeprazole, on intragastric pH in healthy Chinese. METHODS Thirty-six healthy volunteers (26 men and 10 women, aged between 20 and 31 years) were enrolled. Subjects were given either esomeprazole 40 mg (n = 18) or rabeprazole 10 mg (n = 18) orally once daily for 5 days during the first dosing period, then the other medicine at the set dosage for the second dosing period. The two periods were separated by a 14-day washout phase. The doses were chosen according to the State Food and Drug Administration of China for the treatment of acid-related diseases. Intragastric pH was continuously monitored for 24 h on days 1 and 5 of each dosing period. CYP2C19 genotypes were analyzed to identify the extensive metabolizers (EM) and poor metabolizers (PM). RESULTS The percentage of time with intragastric pH >4 was significantly higher (P < 0.001) in subjects receiving esomeprazole than in those receiving rabeprazole in the first 4 h after administration of the first dose (70.65% vs 44.87%), at 24 h on day 1 (73.7% vs 54.8%) and at 24 h on day 5 (84.2% vs 76.2%). The median intragastric pH was also higher in subjects receiving esomeprazole than in those receiving rabeprazole in the first 6 h, day 1 and day 5 (P <or= 0.001). The percentage of subjects with intragastric pH >4 for at least 16 h on day 1 (63.9% vs 33.3%) and on day 5 (88.9% vs 61.1%) was higher after administration of esomeprazole than after rabeprazole (both P < 0.05). On genotype analysis, 28 of the subjects were EM and eight were PM. Those who were PM tended to have a higher, albeit not statistically significant, percentage of time with intragastric pH >4 and the median 24-h intragastric pH than those who were EM. Both drugs were well tolerated. CONCLUSIONS Esomeprazole 40 mg orally once daily is more effective and faster in increasing intragastric pH than rabeprazole 10 mg orally once daily, and thus offers a potential for improved efficacy in acid-related diseases.
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Affiliation(s)
- Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China.
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Shimatani T, Inoue M, Kuroiwa T, Moriwaki M, Xu J, Ikawa K, Morikawa N, Tazuma S. Which has superior acid-suppressive effect, 10 mg omeprazole once daily or 20 mg famotidine twice daily? Effects of single or repeated administration in Japanese Helicobacter pylori-negative CYP2C19 extensive metabolizers. Dig Dis Sci 2007; 52:390-5. [PMID: 17211705 DOI: 10.1007/s10620-006-9490-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2006] [Accepted: 06/14/2006] [Indexed: 12/29/2022]
Abstract
Low-dose omeprazole is superior to full-dose famotidine in maintenance therapy for gastroesophageal reflux disease, whereas "on-demand" famotidine is more effective for relief of episodes of heartburn. To explain this apparent discrepancy, intragastric pH was measured for 24-hr seven times in eight Japanese Helicobacter pylori-negative cytochrome P450 2C19 extensive metabolizers; on Days 1, 8, and 15 of repeated administration of 10 mg of omeprazole once daily and of 20 mg of famotidine twice daily and before medication. During repeated administration of omeprazole, mean intragastric pH and % time that intragastric pH > 4.0 were significantly higher and became greater. With famotidine, although these parameters were significantly higher, the degrees became smaller. Consequently, acid-suppressive effect was in the order; omeprazole < famotidine on Day 1, omeprazole approximately famotidine on Day 8, and omeprazole >famotidine on Day 15. This discrepancy possibly results from the "potentiation" of acid-suppressive effect of omeprazole and the "tolerance" phenomenon in respect to famotidine.
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Affiliation(s)
- Tomohiko Shimatani
- Department of General Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Hiroshima, Japan.
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Ji S, Kim HS, Kim JW, Jee MK, Park KW, Uh Y, Lee DK, Song JS, Baik SK, Kwon SO. Comparison of the efficacy of rabeprazole 10 mg and omeprazole 20 mg for the healing rapidity of peptic ulcer diseases. J Gastroenterol Hepatol 2006; 21:1381-7. [PMID: 16911680 DOI: 10.1111/j.1440-1746.2006.04314.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
AIM Rabeprazole has been known to inhibit H(+)/K(+)-ATPase more rapidly than omeprazole, the prototype proton pump inhibitor (PPI). The aim of this study was to demonstrate equivalence between low-dose rabeprazole 10 mg and omeprazole 20 mg for the healing rapidity of active peptic ulcer and for improvement of symptoms. Also, the effect of CYP2C19 genotypes on ulcer healing rapidity was investigated. METHODS A total of 112 patients with active peptic ulcer were randomized to receive either rabeprazole 10 mg q.d. or omeprazole 20 mg q.d. for 6 weeks. The remaining ratios (%) and complete healing of the ulcer were determined by endoscopy at 1 week and 6 weeks of treatment. The severity of ulcer pain was also investigated during treatment. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS The remaining ratio of peptic ulcers after 1 week and the complete healing rate after 6 weeks in the rabeprazole versus omeprazole group were 45.5% versus 50.3% (P = 0.475) and 80.6% versus 87.0% (P = 0.423), respectively. CYP2C19 genotypes had no effect on the remaining ratio of peptic ulcers after 1 week and the healing rate of peptic ulcers after 6 weeks in both groups. The proportions of patients with symptom improvement or resolution were comparable between the two groups. CONCLUSION Low-dose rabeprazole 10 mg has a similar efficacy for the healing rapidity of active peptic ulcer disease and symptom improvement compared with standard-dose omeprazole 20 mg.
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Affiliation(s)
- Sangwon Ji
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, South Korea
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Doki K, Homma M, Kuga K, Kusano K, Watanabe S, Yamaguchi I, Kohda Y. Effect of CYP2D6 genotype on flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia. Eur J Clin Pharmacol 2006; 62:919-26. [PMID: 16944116 DOI: 10.1007/s00228-006-0188-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2006] [Accepted: 07/18/2006] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To examine the effect of CYP2D6 genotype on the pharmacokinetics of flecainide, we conducted a population pharmacokinetic analysis of the data collected during routine therapeutic drug monitoring of Japanese patients with supraventricular tachyarrhythmia. METHODS Population analysis was performed on retrospective data from 58 patients with normal kidney and liver function treated with oral flecainide for supraventricular tachyarrhythmia. Serum concentrations of flecainide were determined by high-performance liquid chromatography. CYP2D6 genotyping for extensive metabolizer (EM), intermediate metabolizer (IM) and poor metabolizer (PM) alleles was conducted by allele-specific polymerase chain reaction (PCR) and stepdown PCR. WinNonMix was used to estimate oral clearance (CL/F) of flecainide with a one-compartment model for first-order absorption. RESULTS Body weight, age, sex, serum creatinine concentration (Scr), and CYP2D6 genotype influenced flecainide pharmacokinetics. The CL/F was affected by age (30% reduction in > or =70 years old) and sex (24% reduction in females). The ratios of CL/F for the five CYP2D6 genotypes were: 1.00 (EM/EM), 0.89 (EM/IM), 0.84 (EM/PM), 0.79 (IM/IM), 0.73 (IM/PM). A model including these five covariates reduced the interpatient variability of CL/F from 32.9% (base model) to 17.8%. Using a Bayesian method we estimated that the CL/F in IMs was significantly lower than in homozygous EMs (0.25+/-0.05 l h(-1) kg(-1) vs. 0.37+/-0.08 l h(-1) kg(-1), P<0.05) among male patients under 70 years old. CONCLUSIONS CYP2D6 genotype, even in IMs, as well as body weight, age, sex, and Scr influence flecainide pharmacokinetics in Japanese patients with supraventricular tachyarrhythmia.
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Affiliation(s)
- Kosuke Doki
- Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ten-nodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan
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Hanioka N, Okumura Y, Saito Y, Hichiya H, Soyama A, Saito K, Ueno K, Sawada JI, Narimatsu S. Catalytic roles of CYP2D6.10 and CYP2D6.36 enzymes in mexiletine metabolism: In vitro functional analysis of recombinant proteins expressed in Saccharomyces cerevisiae. Biochem Pharmacol 2006; 71:1386-95. [PMID: 16527257 DOI: 10.1016/j.bcp.2006.01.019] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2006] [Revised: 01/31/2006] [Accepted: 01/31/2006] [Indexed: 11/28/2022]
Abstract
Cytochrome P450 2D6 (CYP2D6) metabolizes approximately one-third of the medicines in current clinical use and exhibits genetic polymorphism with interindividual differences in metabolic activity. To precisely investigate the effect of CYP2D6*10B and CYP2D6*36 frequently found in Oriental populations on mexiletine metabolism in vitro, CYP2D6 proteins of wild-type (CYP2D6.1) and variants (CYP2D6.10 and CYP2D6.36) were heterologously expressed in yeast cells and their mexiletine p- and 2-methyl hydroxylation activities were determined. Both variant CYP2D6 enzymes showed a drastic reduction of CYP2D6 holo- and apoproteins compared with those of CYP2D6.1. Mexiletine p- and 2-methyl hydroxylation activities on the basis of the microsomal protein level at the single substrate concentration (100 microM) of variant CYP2D6s were less than 6% for CYP2D6.10 and 1% for CYP2D6.36 of those of CYP2D6.1. Kinetic analysis for mexiletine hydroxylation revealed that the affinity toward mexiletine of CYP2D6.10 and CYP2D6.36 was reduced by amino acid substitutions. The Vmax and Vmax/Km values of CYP2D6.10 on the basis of the microsomal protein level were reduced to less than 10% of those of CYP2D6.1, whereas the values on the basis of functional CYP2D6 level were comparable to those of CYP2D6.1. Although it was impossible to estimate the kinetic parameters for the mexiletine hydroxylation of CYP2D6.36, the metabolic ability toward mexiletine was considered to be poorer not only than that of CYP2D6.1 but also than that of CYP2D6.10. The same tendency was also observed in kinetic analysis for bufuralol 1''-hydroxylation as a representative CYP2D6 probe. These findings suggest that CYP2D6*36 has a more drastic impact on mexiletine metabolism than CYP2D6*10.
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Affiliation(s)
- Nobumitsu Hanioka
- Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan
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Wong JOY, Leung SP, Mak T, Ng RMK, Chan KT, Hon-Kee Cheung H, Choi WK, Lai J, Wai-Kiu Tsang A. Plasma clozapine levels and clinical response in treatment-refractory Chinese schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:251-64. [PMID: 16316716 DOI: 10.1016/j.pnpbp.2005.10.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2005] [Indexed: 11/16/2022]
Abstract
PURPOSE To evaluate clinical efficacy of clozapine in relation with its plasma level in a group of Chinese patients with treatment-resistant schizophrenia. In addition, the relationship between plasma level and side effects were examined. METHOD Fifty-one patients with treatment-resistant schizophrenia were put on a fixed dose of clozapine at 300 mg/day for 6 weeks. Non-responders to week 6 received 500 mg/day in subsequent 6 weeks. Responders to week 6 continued to receive 300 mg/day. Clozapine plasma levels were checked at weeks 6 and 12. FINDINGS No association was found between clozapine plasma level, response and side effects. Sodium valproate was found to elevate clozapine plasma level while lowering norclozapine/clozapine ratio. CONCLUSION Clozapine plasma level was not found to be associated with response and side effect in Chinese treatment-resistant schizophrenic patients. Various explanations were postulated for the lack of relationship observed between clozapine plasma level and response in this population.
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Affiliation(s)
- Jessica Oi-Yin Wong
- Castle Peak Hospital, 15 Tsing Chung Koon Road, Tuen Mun, New Territories, Hong Kong, PR China.
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Abstract
BACKGROUND AND OBJECTIVE Considerable ethnic differences have been reported in the incidence of the poor metaboliser (PM) genotype of cytochrome P450 (CYP) 2C19. The frequency of this genotype was found to be much higher in Oriental persons (13-23%) than in American or European populations (3-5%). There are, however, no valid data published for Arabic subjects. The present study was conducted to evaluate pharmacokinetic parameters of omeprazole after a single dose in healthy Jordanian Arabic subjects and to compare the results with data published for other populations. METHODS Seventy-four healthy male Jordanian Arabic volunteers contributed to the study, which was performed at Al Essra Hospital in Amman, Jordan. After an overnight fast, omeprazole was administered as a single Losec 20mg capsule. A total of 20 blood samples were collected over a 10-hour period after administration. Omeprazole pharmacokinetic parameters were determined from the plasma concentration-time profiles using the WinNonlin software. Kolmogorov-Smirnov's test and probit plots of omeprazole area under the plasma concentration-time curve (AUC) data were used to analyse the frequency distribution of phenotypic data. RESULTS The mean pharmacokinetic parameters and their corresponding coefficient of variation (CV%) for peak plasma concentration (Cmax), AUC from time zero to infinity (AUCinfinity), time to reach Cmax (tmax), apparent oral clearance (CL/F) and elimination half-life (t(1/2)) were 314.96 ng/mL (56%), 923.2 ng . h/mL (108.6%), 2.1h (44%), 0.66 L/h/kg (92%) and 1.5 h (56.6%), respectively. Interindividual differences in the current study were high for all pharmacokinetic parameters, yet comparable to CVs reported in nonphenotyped subjects identified within other ethnic groups (40.3-159% for AUC and 39-48.2% for Cmax). The frequency distribution of all parameters, particularly the AUC, was shown to be trimodal. This has proposed the presence of three distinct phenotypes, designated as extensive metabolisers (EMs), slow-extensive metabolisers (SEMs), and PMs, with corresponding frequency of 36.5%, 39.2% and 24.3%, respectively. After stratification, the relative mean AUCs of omeprazole in EMs, SEMs and PMs were 1 : 2.7 : 9.3 (all p < 0.001). Accordingly, the CL/F of omeprazole showed a ratio of 9.8 : 3.6 : 1 for three phenotype groups, respectively. For other pharmacokinetic parameters including Cmax, t1/2, AUC normalised for bodyweight (AUCN), Cmax/dose and AUC/dose, there were also significant differences between the three groups. CONCLUSIONS The current pharmacokinetic study revealed that the majority of the Jordanian Arabics seemed to be more properly classified within the EM phenotype. More specifically, the observed metabolic rates of heterozygous and homozygous Jordanian Arabic EMs were more comparable to those of Caucasian EMs than Oriental EMs. Consequently, higher dosage requirements can be expected among most of the Jordanian Arabics. Yet, the incidence of PMs is significant and they seemed to exhibit a similar pharmacokinetic pattern to Chinese PMs in terms of long-term exposure (clearance and AUC) as well as short-term exposure (Cmax) parameters, after adjustment for dose and bodyweight. Therefore, further clinical application of CYP2C19 polymorphism is anticipated in Jordanian Arabic mixed population, particularly if long-term use of omeprazole is intended.
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Ferraro TN, Buono RJ. The relationship between the pharmacology of antiepileptic drugs and human gene variation: an overview. Epilepsy Behav 2005; 7:18-36. [PMID: 15979945 DOI: 10.1016/j.yebeh.2005.04.010] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2005] [Accepted: 04/20/2005] [Indexed: 10/25/2022]
Abstract
Individual differences in clinical responsiveness to antiepileptic drugs are due to a complex interaction between environmental factors and genetic variation. Considerable interest has arisen in exploiting advances in molecular genetics to improve drug therapy for epilepsy and many other diseases; however, practical application of pharmacogenetics has been difficult to realize. Attempts to define gene variants that are associated with therapeutic (or adverse) effects of antiepileptic drugs rely currently on the prior identification of candidate genes and the subsequent evaluation of the distribution of allelic variants between individuals who have a "good" versus a "poor" clinical response. Many factors can adversely affect interpretation of such data, and careful consideration must be given to the design of genetic association studies involving candidate genes. Candidate genes may be identified in a number of ways; however, for studies of drugs, application of knowledge derived from basic pharmacology can suggest focused and testable hypotheses that are based on the fundamental principles of drug action. Thus, studies of genetic variation as they relate to proteins involved in antiepileptic drug kinetics and dynamics will identify key polymorphisms in endogenous molecules that determine degrees of drug efficacy and toxicity. Delineation of these effects in the coming years will promote enhanced success in the treatment of epilepsy.
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Affiliation(s)
- Thomas N Ferraro
- Departments of Psychiatry and Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Shimatani T, Inoue M, Kuroiwa T, Xu J, Tazuma S, Horikawa Y, Nakamura M. Acid-suppressive efficacy of a reduced dosage of rabeprazole: comparison of 10 mg twice daily rabeprazole with 20 mg twice daily rabeprazole, 30 mg twice daily lansoprazole, and 20 mg twice daily omeprazole by 24-hr intragastric pH-metry. Dig Dis Sci 2005; 50:1202-6. [PMID: 16047460 DOI: 10.1007/s10620-005-2760-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Rabeprazole achieves more potent acid suppression than other proton pump inhibitors. Therefore it is administered at reduced as well as high dosages in eradication therapy for Helicobacter pylori; however, there is incomplete assessment of the efficacy of a reduced dosage of rabeprazole as might be employed in therapy. In this study, we evaluated acid-suppressive efficacy of a reduced dosage of rabeprazole on day 7 by 24-hr pH-metry in 10 healthy male cytochrome P-450 2C19 extensive metabolizers without Helicobacterpylori infection and compared the results with those of high dosages of rabeprazole, lansoprazole, and omeprazole. Median intragastric pH value, pH >3 holding time ratio (pH>3HT), pH>4HT, pH>5HT, pH>6HT, and pH>7HT for 24 hr with rabeprazole, 10 mg twice daily, were not significantly different from those of rabeprazole, 20 mg twice daily, lansoprazole, 30 mg twice daily, and omeprazole, 20 mg twice daily. In conclusion, for acid-suppressive efficacy, a reduced dosage of rabeprazole is comparable to high dosages of rabeprazole, lansoprazole, and omeprazole.
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Affiliation(s)
- Tomohiko Shimatani
- Department of General Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
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Ohkusa T, Maekawa T, Arakawa T, Nakajima M, Fujimoto K, Hoshino E, Mitachi Y, Hamada S, Mine T, Kawahara Y, Nagai T, Aoyama N, Yoshida N, Tadokoro K, Chida N, Konda Y, Seno H, Shimatani T, Inoue M, Sato N. Effect of CYP2C19 polymorphism on the safety and efficacy of omeprazole in Japanese patients with recurrent reflux oesophagitis. Aliment Pharmacol Ther 2005; 21:1331-9. [PMID: 15932363 DOI: 10.1111/j.1365-2036.2005.02486.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND The polymorphic enzyme cytochrome P450 2C19 affects omeprazole metabolism. This influence on metabolism might affect serum gastrin levels, and safety, during long-term treatment of reflux oesophagitis. AIM To examine the relationship between cytochrome P450 2C19 genotype and the safety profile of long-term omeprazole treatment. METHODS A total of 119 Japanese patients with recurrent reflux oesophagitis underwent cytochrome P450 2C19 genotyping prior to receiving daily omeprazole 10 mg or 20 mg for 6-12 months, during which adverse event frequency, serum gastrin levels and endoscopic findings were monitored. RESULTS The incidences of adverse events, serious adverse events and adverse events leading to withdrawal did not differ between homozygous extensive metabolizer (n = 46), heterozygous extensive metabolizer (n = 53) or poor metabolizer (n = 20) groups. In all genotype groups, serum gastrin increased during the first 3 months of dosing but stabilized thereafter. No significant differences were seen either in the rate of reflux oesophagitis healing or symptom improvement among genotype groups. CONCLUSIONS Long-term treatment with omeprazole was well-tolerated in Japanese patients, irrespective of their cytochrome P450 2C19 metabolic genotype, indicating that dose adjustment depending on metabolic genotype is not required during treatment with omeprazole.
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Affiliation(s)
- T Ohkusa
- Juntendo University School of Medicine, Hongo, Tokyo, Japan
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Yamamoto T, Hagima N, Nakamura M, Kohno Y, Nagata K, Yamazoe Y. Prediction of differences in in vivo oral clearance of N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl] ethylamine monohydrochloride (NE-100) between extensive and poor metabolizers from in vitro metabolic data in human liver microsomes lacking CYP2D6 activity and recombinant CYPs. Xenobiotica 2005; 34:687-703. [PMID: 15672756 DOI: 10.1080/00498250412331281070] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
1. It has previously been reported that N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride (NE-100) was predominantly metabolized by cytochrome P450 (CYP) 2D6 in human liver microsomes (HLM). In the present study, the contribution of CYP forms involved in the formation of the major metabolites of NE-100 in human liver lacking CYP2D6 activity (PM-HLM) has been predicted by use of in vitro kinetic data on recombinant CYPs microsomes (rCYPs). 2. In PM-HLM, NE-100 is predicted to be metabolized to N-despropyl-NE-100 (NE-098), p-hydroxy-NE-100 (NE-152) and m-hydroxyl-NE-100 (NE-163), but not to O-demethy-NE-100 (NE-125), which is a major metabolite in pooled human liver microsomes (EM-HLM). The relative activity factor approach assumed that NE-098 formation is predominantly catalysed by CYP3A4 and CYP2C9 and the NE-152+163mix (a mixture of two hydroxylated metabolites, NE-152 and NE-163) formation is only catalysed by CYP3A4. 3. The predicted contribution rates of CYP3A4 and CYP2C9 for NE-098 formation were 58.1 and 34.6%, respectively, in PM-HLM. These predicted results were strongly supported by kinetic and inhibition studies using PM-HLM. The intrinsic clearance of NE-100 predicted from rCYPs (the predicted CLint-HLM-total) corresponded to those observed from EM- and PM-HLM (the observed CLint-HLM). 4. The in vivo oral clearance (CLoral) of NE-100 in extensive metabolizers and poor metabolizers of CYP2D6 was predicted to be 50times higher in extensive metabolizers than poor metabolizers using in vitro-in vivo scaling method based on the dispersion model. These data suggest that polymorphism of CYP2D6 might greatly affect NE-100 metabolism in vivo.
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Affiliation(s)
- T Yamamoto
- Department of Drug Metabolism, Medicinal Research Laboratory, Taisho Pharmaceutical Co, Ltd, Kita-ku, Saitama-shi, Saitama 331-9530, Japan.
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Roh HK, Kim PS, Lee DH, Tybring G, Sagar M, Park CS, Seensalu R, Bertilsson L. Omeprazole treatment of Korean patients: effects on gastric pH and gastrin release in relation to CYP2C19 geno- and phenotypes. Basic Clin Pharmacol Toxicol 2005; 95:112-9. [PMID: 15447734 DOI: 10.1111/j.1742-7843.2004.950302.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
This study aimed to investigate the effect of omeprazole on intragastric pH and gastrin release as well as the plasma concentration of omeprazole in relation to CYP2C19 genotypes after repeated doses in Korean patients. Twenty-six Korean patients with acid related disease were genotyped for CYP2C19 by allele specific PCR (wt/wt, CYP2C19*1/*1; wt/mut, CYP2C19*1/*2 or *1/*3; mut/mut, CYP2C19*2/*2, *2/*3 or *3/*3). Intragastric pH was monitored during 24 hr, and the plasma concentrations of omeprazole, hydroxyomeprazole, omeprazole sulfone and meal-stimulated gastrin were measured during 4 hr before and after 8 consecutive daily doses of 20 mg omeprazole. Unexpectedly the AUCs of omeprazole in the three genotypes were similarly high on Day 8. The mean 24 hr pH increased significantly in all three genotypes (paired t-test; P<0.0001), and the AUCs (4 hr) of gastrin in all patients increased markedly from 129+/-73 to 298+/-142 pMhr (P<0.0001). However, there was no statistically significant difference between the three genotypes in the mean pH and gastrin AUCs on Day 8. After 8 consecutive doses of 20 mg omeprazole, the gastric pH and the plasma gastrin were increased significantly in all three CYP2C19 genotypes, which were confirmed by high plasma concentrations of omeprazole in all three genotype groups. We suggest that the reason why the wt/wt had high concentrations of omeprazole similar to those in the other two genotype groups is that some of them were old with low CYP2C19 activity. In these patients omeprazole accumulated from the first to the eighth dose similar to that in the heterozygotes.
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Affiliation(s)
- Hyung-Keun Roh
- Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
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Kim K, Johnson JA, Derendorf H. Differences in drug pharmacokinetics between East Asians and Caucasians and the role of genetic polymorphisms. J Clin Pharmacol 2005; 44:1083-105. [PMID: 15342610 DOI: 10.1177/0091270004268128] [Citation(s) in RCA: 159] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Interethnic variability in pharmacokinetics can cause unexpected outcomes such as therapeutic failure, adverse effects, and toxicity in subjects of different ethnic origin undergoing medical treatment. It is important to realize that both genetic and environmental factors can lead to these differences among ethnic groups. The International Conference on Harmonization (ICH) published a guidance to facilitate the registration of drugs among ICH regions (European Union, Japan, the United States) by recommending a framework for evaluating the impact of ethnic factors on a drug's effect, as well as its efficacy and safety at a particular dosage and dosage regimen. This review focuses on the pharmacokinetic differences between East Asians and Caucasians. Differences in metabolism between East Asians and Caucasians are common, especially in the activity of several phase I enzymes such as CYP2D6 and the CYP2C subfamily. Before drug therapy, identification of either the genotype and/or the phenotype for these enzymes may be of therapeutic value, particularly for drugs with a narrow therapeutic index. Furthermore, these differences are relevant for international drug approval when regulatory agencies must decide if they accept results from clinical trials performed in other parts of the world.
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Affiliation(s)
- Kiman Kim
- Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA
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