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Kido K, Guglin M. Why Bisoprolol? A Neglected Beta-Blocker in the U.S. J Pharm Pract 2025; 38:285-286. [PMID: 39675838 DOI: 10.1177/08971900241308623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024]
Affiliation(s)
- Kazuhiko Kido
- Clinical Associate Professor, Department of Clinical Pharmacy, West Virginia University School of Pharmacy, Morgantown, WV, USA
| | - Maya Guglin
- Section Chief and Professor of Medicine, Heart Failure/Transplant, Rutgers University, New Brunswick, NJ, USA
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Hu J, Mei H, Su NY, Sun WJ, Zhang DK, Fan LL, He P, Pan J, Wang XW, Zou PY, Liu YX, Guo Y, Lan CH. Eradication rates of Helicobacter pylori in treatment-naive patients following 14-day vonoprazan-amoxicillin dual therapy: A multicenter randomized controlled trial in China. Helicobacter 2023:e12970. [PMID: 37160689 DOI: 10.1111/hel.12970] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/26/2023] [Accepted: 03/02/2023] [Indexed: 05/11/2023]
Abstract
BACKGROUND Potassium-competitive acid blockers (P-CAB) are recommended for the treatment of Helicobacter pylori infections, but dual therapy of P-CAB with amoxicillin has been poorly studied. The current study compared the efficacy, adverse reactions, compliance, and effects on gut microbiota of 14-day vonoprazan-amoxicillin (VA) dual therapy with esomeprazole, bismuth potassium citrate, amoxicillin, and metronidazole (EBAM) quadruple therapy in treatment-naive patients with H. pylori. MATERIALS AND METHODS This was a multicenter, open-label, randomized, and controlled, non-inferiority study. Patients (n = 194) enrolled from six centers were randomly divided into either the VA or EBAM group. H. pylori eradication was determined using 13 C urea breath tests (UBT) 4-6 weeks post-treatment. Fecal samples were collected, and gut microbial populations were analyzed by 16S rDNA and metagenomic sequencing technology. RESULTS Eradication rates of H. pylori in the VA and EBAM groups were 88.7% and 91.8%, respectively, according to intention-to-treat (ITT) analysis; 95.6% and 96.7% with per-protocol (PP) analysis; and 94.5% and 96.7% with modified ITT (mITT) analysis (all p > 0.05). The incidence of adverse reactions in the VA group was significantly lower compared to the EBAM group, and compliance within both groups was good. There was no difference in α-diversity or microbial composition in the VA and EBAM groups at one-month post-treatment compared to baseline, except for a markedly reduced abundance of Bacteroides in the EBAM group. CONCLUSION VA therapy achieved excellent eradication rates with low adverse reactions, good compliance, and little impact on gut microbiota. VA therapy should be recommended as a first-line treatment against H. pylori.
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Affiliation(s)
- Jie Hu
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Hao Mei
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Na-Yun Su
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Wen-Jing Sun
- Department of Gastroenterology, The 13th People's Hospital of Chongqing, Chongqing, China
| | - De-Kui Zhang
- Department of Gastroenterology, Lanzhou University Second Hospital, Lanzhou, China
| | - Li-Lin Fan
- Department of Gastroenterology, The Second People's Hospital of Chongqing, Chongqing, China
| | - Ping He
- Department of Gastroenterology, Yongchuan Hospital Affiliated to Chongqing Medical University, Chongqing, China
| | - Jie Pan
- Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou, China
| | - Xing-Wei Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Pei-Ying Zou
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yu-Xiang Liu
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Yan Guo
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Chun-Hui Lan
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, 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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Tan EY, Bharwani L, Chia YH, Soong RCT, Lee SSY, Chen JJC, Chan PMY. Impact of cytochrome P450 2D6 polymorphisms on decision-making and clinical outcomes in adjuvant hormonal therapy for breast cancer. World J Clin Oncol 2022; 13:712-724. [PMID: 36160461 PMCID: PMC9476606 DOI: 10.5306/wjco.v13.i8.712] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/08/2021] [Accepted: 07/18/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND There are concerns that tamoxifen is less effective in Asian women because of the high prevalence of impaired function cytochrome P450 2D6 (CYP2D6) polymor-phisms.
AIM To evaluate how knowledge of CYP2D6 genotype impacted the choice of hormonal agent and how CYP2D6 genotype and agent were associated with clinical outcomes.
METHODS Eighty-two women were recruited. Seventy-eight completed CYP2D6 genotyping and were categorized into poor, intermediate (IM) and extensive or ultra metabolizer phenotypes. Women with poor metabolizer and IM phenotypes were recommended aromatase inhibitors as the preferred agent.
RESULTS More than 70% of the women had an IM phenotype, 32% an extensive or ultra metabolizer phenotype, and 0% had a poor metabolizer phenotype. Regardless of genotype, more women opted for aromatase inhibitors. Overall, 80% of women completed 5 years of hormonal therapy. Five women developed recurrence, 3 contralateral breast cancer, 5 died, and 1 was diagnosed with a second primary cancer. Five-year recurrence-free and overall survival were slightly better in women with the extensive or ultra metabolizer phenotype compared to those with the IM phenotype, though not statistically significant [P = 0.743, hazard ratio (HR): 1.441, 95% confidence interval (CI): 0.191 to 10.17 and P = 0.798, HR: 1.327, 95%CI: 0.172 to 9.915, respectively]. Women receiving aromatase inhibitors also appeared to have a better, but also nonsignificant, 5-year recurrence-free and overall survival (P = 0.253, HR: 0.368, 95%CI: 0.031 to 0.258 and P = 0.292, HR: 0.252, 95%CI: 0.005 to 4.951, respectively).
CONCLUSION The IM phenotype was highly prevalent but was not associated with clinical outcome.
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Affiliation(s)
- Ern-Yu Tan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
- Lee Kong Chian School of Medicine, Singapore 308232, Singapore
- Institute of Molecular and Cell Biology, A*STAR, Singapore 138673, Singapore
| | - Lavina Bharwani
- Department of Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Yee-Hong Chia
- Department of Medical Oncology, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Richie C T Soong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 119077, Singapore
| | - Sherylyn S Y Lee
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Juliana J C Chen
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
| | - Patrick M Y Chan
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Suroowan S, Abdallah HH, Mahomoodally MF. Herb-drug interactions and toxicity: Underscoring potential mechanisms and forecasting clinically relevant interactions induced by common phytoconstituents via data mining and computational approaches. Food Chem Toxicol 2021; 156:112432. [PMID: 34293424 DOI: 10.1016/j.fct.2021.112432] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 06/28/2021] [Accepted: 07/17/2021] [Indexed: 01/05/2023]
Abstract
Herbals in the form of medicine are employed extensively around the world. Herbal and conventional medicine combination is a potentially dangerous practice mainly in comorbid, hepato insufficient and frail patients leading to perilous herb-drug interactions (HDI) and toxicity. This study features potential HDI of 15 globally famous plant species through data mining and computational methods. Several plant species were found to mimic warfarin. Phytochemicals from M. charantia induced hypoglycemica. M. chamomila and G. biloba possessed anticoagulant activities. S. hispanica reduces postprandial glycemia. R. officinalis has been reported to inhibit the efflux of anticancer substrates while A. sativum can boost the clearance of anticancer agents. P. ginseng can alter blood coagulation. A cross link of the biological and in silico data revealed that a plethora of herbal metabolites such as ursolic and rosmarinic acid among others are possible/probable inhibitors of specific CYP450 enzymes. Consequently, plant species/metabolites with a given pharmacological property/metabolizing enzyme should not be mixed with drugs having the same pharmacological property/metabolizing enzyme. Even if combined with drugs, herbal medicines must be used at low doses for a short period of time and under the supervision of a healthcare professional to avoid potential adverse and toxic effects.
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Affiliation(s)
- Shanoo Suroowan
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Réduit, Mauritius
| | - Hassan Hadi Abdallah
- Department of Chemistry, College of Education, Salahaddin University-Erbil, Erbīl, Iraq
| | - Mohamad Fawzi Mahomoodally
- Department of Health Sciences, Faculty of Medicine and Health Sciences, University of Mauritius, Réduit, Mauritius.
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CYP2D6 phenotype explains reported yohimbine concentrations in four severe acute intoxications. Arch Toxicol 2021; 95:2867-2870. [PMID: 34027562 PMCID: PMC8298364 DOI: 10.1007/s00204-021-03082-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/17/2021] [Indexed: 11/28/2022]
Abstract
The indole alkaloid yohimbine is an alpha-2 receptor antagonist used for its sympathomimetic effects. Several cases of yohimbine intoxication have been reported and the most recent one involved four individuals taking a yohimbine-containing drug powder. All individuals developed severe intoxication symptoms and were admitted to the hospital. Even though all individuals were assumed to have taken the same dose of the drug powder, toxicology analyses revealed yohimbine blood concentrations of 249–5631 ng/mL, amounting to a 22-fold difference. The reason for this high variability remained to be elucidated. We used recently reported knowledge on the metabolism of yohimbine together with state-of-the art nonlinear mixed-effects modelling and simulation and show that a patient’s cytochrome P450 2D6 (CYP2D6) phenotype can explain the large differences observed in the measured concentration after intake of the same yohimbine dose. Our findings can be used both for the identification of safe doses in therapeutic use of yohimbine and for an explanation of individual cases of overdosing.
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Batistaki C, Chrona E, Kostroglou A, Kostopanagiotou G, Gazouli M. CYP2D6 Basic Genotyping of Patients with Chronic Pain Receiving Tramadol or Codeine. A Study in a Greek Cohort. PAIN MEDICINE (MALDEN, MASS.) 2020; 21:3199-3204. [PMID: 32443139 DOI: 10.1093/pm/pnaa122] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
OBJECTIVE To assess CYP2D6 genotype prevalence in chronic pain patients treated with tramadol or codeine. DESIGN Prospective cohort study. SETTING General hospital, pain management unit. SUBJECTS Patients with chronic pain, treated with codeine or tramadol. METHODS Patients' pain was assessed at baseline (numeric rating scale [NRS]; 0-10). Prescription of codeine or tramadol was selected randomly. The assessment of patients' response to the drug in terms of pain relief and adverse effects was performed after 24 hours. Reduction of pain intensity of >50% or an NRS <4 was considered a positive response. Patients' blood samples were collected during the first visit. Genotyping for the common variants CYP2D6 *2, *3, *4, *5, *6, *9, *10, *14, and *17 was performed, and alleles not carrying any polymorphic allele were classified as CYP2D6*1 (wild-type [wt]). RESULTS Seventy-six consecutive patients were studied (20 males, 56 females), aged 21-85 years. Thirty-four received tramadol and 42 codeine. The main genotypes of CYP2D6 identified were the wt/wt (35.5%), the *4/wt (17.1%), and the *6/wt (10.5%). Adverse effects were common, especially in carriers of *9/*9, *5/*5, *5/*4, and *10/*10, as well as in variants including the 4 allele (*4/*1 [38.4%] and *4/*4 [42.8%]). CONCLUSIONS Genotyping can facilitate personalized pain management with opioids, as specific alleles are related to decreased efficacy and adverse effects.
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Affiliation(s)
- Chrysanthi Batistaki
- 2nd Department of Anaesthesiology, Faculty of Medicine, National, Kapodistrian University of Athens, Pain Management Unit, "Attikon" Hospital, Athens, Greece
| | - Eleni Chrona
- Department of Anaesthesiology, General Hospital of Nikea, "Ag. Panteleimon," Piraeus, Greece
| | - Andreas Kostroglou
- 2nd Department of Anaesthesiology, Faculty of Medicine, National, Kapodistrian University of Athens, Pain Management Unit, "Attikon" Hospital, Athens, Greece
| | - Georgia Kostopanagiotou
- 2nd Department of Anaesthesiology, Faculty of Medicine, National, Kapodistrian University of Athens, Pain Management Unit, "Attikon" Hospital, Athens, Greece
| | - Maria Gazouli
- Laboratory of Biology, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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Li LJ, Chong Q, Wang L, Cher GB, Soo RA. Different treatment efficacies and side effects of cytotoxic chemotherapy. J Thorac Dis 2020; 12:3785-3795. [PMID: 32802458 PMCID: PMC7399437 DOI: 10.21037/jtd.2019.08.63] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Differences in efficacy and toxicity between Asian and Caucasian patients with lung cancer treated with systemic chemotherapy is increasingly recognised. This is a major concern in the clinical setting as it influences outcomes and affect international harmonization of drug development. Interindividual variability of pharmacokinetics, where different genetic polymorphisms affect drug metabolism, transport, and receptor binding may account for the ethnic differences. Treatment efficacy and outcomes may also be explained by differences in diet and lifestyle, access to healthcare, cultural barriers and environmental exposure. Efforts made to design prospective studies investigating ethnic specific determinants to systemic therapy and individualise lung cancer treatment based on genetic makeup of patient are important.
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Affiliation(s)
- Low-Jia Li
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore
| | - Qingyun Chong
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Goh Boon Cher
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore.,Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Pharmacology, National University of Singapore, Singapore, Singapore
| | - Ross A Soo
- Department of Haematology-Oncology, National University Hospital, Singapore, Singapore
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Almeman AA. Major CYP450 polymorphism Among Saudi Patients. Drug Metab Lett 2020; 14:17-24. [PMID: 32703145 DOI: 10.2174/1872312814666200722122232] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Revised: 06/24/2020] [Accepted: 07/01/2020] [Indexed: 01/22/2023]
Abstract
BACKGROUND Cytochrome P450 (CYP) contributes to a huge collection of medicinal products' Phase I metabolization. We aimed to summarize and investigate the current evidence regarding the frequency of CYP2D6, CYP2C9, CYP2C19, MDR1 in Saudi Arabia. METHODS A computerized search in four databases was done using the relevant keywords. Screening process was done in two steps; title and abstract screening and full-text screening. Data of demographic and characteristics of included studies and patients was extracted and tabulated. RESULTS Ten studies were eligible for our criteria and were included in this systematic review. Age of participants ranged between 17-65 years. Only two subjects showed PM phenotype of CYP2C19 in Saudi population. The most frequent alleles were CYP2C19*1 (62.9%), CYP2C19*2 (11.2%-32%), and CYP2C19*17 (25.7%). The CYP2C19m1 was observed in 97 cases of extensive metabolizing (EM) phenotype CYP2C19. Concerning the CYP2C9, the most frequent alleles were CYP2C9*1 and CYP2C9*2, and the most frequent genotype was CYP2C9*1*1. The CYP2D6*41 allele and C1236T MDR1 were the most frequent allele in this population. CONCLUSION The current evidence suggests that Saudi Arabians resembled European in the frequency of CYP2C19, Caucasians in both the incidence of CYP2C9 and CYP2C19m1 and absence of CYP2C19m2. The CYP2D6*41 allele frequency in Saudi Arabians is relatively high. We recommend a further research to evaluate the basic and clinical relevance of gene polymorphism in such ethnicity.
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Affiliation(s)
- Ahmad Abdulrahman Almeman
- Clinical pharmacology and therapeutics Department, Qassim University, Buraydah, Qassim. Saudi Arabia
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10
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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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Pharmacogenomics in Psychiatric Disorders. Pharmacogenomics 2019. [DOI: 10.1016/b978-0-12-812626-4.00007-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Abstract
BACKGROUND Food/Herb-drug interactions have become a major problem in health care. These interactions can lead to loss of therapeutic efficacy or toxic effects of drugs. AREAS OF UNCERTAINTY To probe the clinical relevance of such interactions, the impact of food/herb intake on the clinical effects of drug administration has to be evaluated. Failure to identify and efficiently manage food-drug interactions can lead to serious consequences. A comprehensive knowledge of the mechanisms that underpin variability in disposition will help optimize therapy. DATA SOURCES Electronic search of literatures from relevant databases were conducted. A total of 58 original scientific reports/review articles were obtained with the search strategy; of which 25 were found eligible to be included in the present review. Required data were extracted from these studies, and their methodologies were assessed. RESULTS AND CONCLUSIONS This review updates our knowledge on clinical food-drug interactions with emphasis on mechanism and clinical implications. Results obtained from literature search identified interactions with selected foods/herbs generated from in vivo and in vitro studies. For example, interaction studies in humans revealed a reduction in the bioavailability of mercaptopurine when taken concurrently with substances containing xanthine oxidase (eg, cow milk); a reduction in the bioavailability of quinine with Garcinia kola; increased bioavailability/toxicity of felodipine, nifedipine, saquinavir, sildenafil with grape juice; increased bioavailability of felodipine, cisapride with red wine and diminished bioavailability of fexofenadine with apple. Pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. By evaluating the dietary patterns of patients and use of prescribed medications, health professionals will be well informed of potential interactions and associated adverse effects.
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Georgopoulos SD, Papastergiou V, Martinez-Gonzalez B, Xirouchakis E, Familias I, Sgouras D, Mentis A, Karatapanis S. Hybrid therapy as first-line regimen for Helicobacter pylori eradication in a high clarithromycin resistance area: a prospective open-label trial. Ann Gastroenterol 2018; 31:205-210. [PMID: 29507467 PMCID: PMC5825950 DOI: 10.20524/aog.2017.0221] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 10/26/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hybrid therapy is a promising first-line regimen for Helicobacter pylori (H. pylori) eradication. We evaluated a hybrid therapy, assessing the impact of antibiotic resistance on eradication outcome. METHODS This was a prospective study that included 155 treatment-naïve patients diagnosed with H. pylori infection by positive CLO-test, confirmed with histology and/or culture. The hybrid therapy consisted of 40 mg esomeprazole and 1 g amoxicillin for 14 days, with the addition of 500 mg clarithromycin and 500 mg metronidazole for the final 7 days (all b.i.d.). Eradication was defined by negative 13C-urea breath test or histology. RESULTS The eradication rates were 85.8% (133/155; 95% confidence interval [CI] 79.4-90.5%) by intention-to-treat and 90.2% (129/143; 95%CI 84.1-94.2%) by per-protocol analysis in a setting of high antibiotic resistance (clarithromycin 25.9%, metronidazole 31.1%, dual resistance 8.9%). Adverse events occurred in 29.7% and 1.3% discontinued treatment because of adverse events. Adherence >90% was achieved in 96.6%. The eradication rate in patients with dual clarithromycin/metronidazole resistance (50%) was markedly lower compared to those with single clarithromycin resistance (91.4%), single metronidazole resistance (90.5%) or dual susceptibility (97.8%). Dual resistance was the only factor to correlate with the failure of hybrid therapy (odds ratio 14.4, 95%CI 3.8-54.9, P=0.0003). CONCLUSIONS Hybrid therapy is an effective and safe first-line regimen in populations with relatively high rates of antibiotic resistance. However, dual clarithromycin/metronidazole resistance may significantly compromise its efficacy.
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Affiliation(s)
- Sotirios D. Georgopoulos
- Gastroenterology Department, Athens Medical, Paleo Faliron Hospital, Athens (Sotirios D. Georgopoulos, Elias Xirouchakis), Greece
| | - Vasilios Papastergiou
- First Department of Internal Medicine, General Hospital of Rhodes, Rhodes (Vasilios Papastergiou, Ioannis Familias, Stylianos Karatapanis), Greece
| | - Beatriz Martinez-Gonzalez
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens (Beatriz Martinez-Gonzalez, Dionysis Sgouras, Andreas Mentis), Greece
| | - Elias Xirouchakis
- Gastroenterology Department, Athens Medical, Paleo Faliron Hospital, Athens (Sotirios D. Georgopoulos, Elias Xirouchakis), Greece
| | - Ioannis Familias
- First Department of Internal Medicine, General Hospital of Rhodes, Rhodes (Vasilios Papastergiou, Ioannis Familias, Stylianos Karatapanis), Greece
| | - Dionysis Sgouras
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens (Beatriz Martinez-Gonzalez, Dionysis Sgouras, Andreas Mentis), Greece
| | - Andreas Mentis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, Athens (Beatriz Martinez-Gonzalez, Dionysis Sgouras, Andreas Mentis), Greece
| | - Stylianos Karatapanis
- First Department of Internal Medicine, General Hospital of Rhodes, Rhodes (Vasilios Papastergiou, Ioannis Familias, Stylianos Karatapanis), Greece
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Stavropoulou E, Pircalabioru GG, Bezirtzoglou E. The Role of Cytochromes P450 in Infection. Front Immunol 2018; 9:89. [PMID: 29445375 PMCID: PMC5797775 DOI: 10.3389/fimmu.2018.00089] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 01/11/2018] [Indexed: 11/27/2022] Open
Abstract
Cytochromes are expressed in many different tissues of the human body. They are found mostly in intestinal and hepatic tissues. Cytochromes P450 (CYPs) are enzymes that oxidize substances using iron and are able to metabolize a large variety of xenobiotic substances. CYP enzymes are linked to a wide array of reactions including and O-dealkylation, S-oxidation, epoxidation, and hydroxylation. The activity of the typical P450 cytochrome is influenced by a variety of factors, such as genus, environment, disease state, herbicide, alcohol, and herbal medications. However, diet seems to play a major role. The mechanisms of action of dietary chemicals, macro- and micronutrients on specific CYP isoenzymes have been extensively studied. Dietary modulation has effects upon the metabolism of xenobiotics. Cytochromes harbor intra- or interindividual and intra- or interethnic genetic polymorphisms. Bacteria were shown to express CYP-like genes. The tremendous metabolic activity of the microbiota is associated to its abundant pool of CYP enzymes, which catalyze phase I and II reactions in drug metabolism. Disease states, intestinal disturbances, aging, environmental toxic effects, chemical exposures or nutrition modulate the microbial metabolism of a drug before absorption. A plethora of effects exhibited by most of CYP enzymes can resemble those of proinflammatory cytokines and IFNs. Moreover, they are involved in the initiation and persistence of pathologic pain by directly activating sensory neurons and inflammatory cytokines.
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Affiliation(s)
| | | | - Eugenia Bezirtzoglou
- Department of Food Science and Technology, Faculty of Agricultural Development, Democritus University of Thrace, Laboratory of Microbiology, Biotechnology and Hygiene, Orestiada, Greece
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15
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Qi G, Li D, Zhang X. Genetic variation of cytochrome P450 in Uyghur Chinese population. Drug Metab Pharmacokinet 2017; 33:55-60. [PMID: 29233455 DOI: 10.1016/j.dmpk.2017.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 11/29/2016] [Accepted: 02/24/2017] [Indexed: 12/01/2022]
Abstract
Interindividual and interethnic variability of drug responses could be attributed to the differences of genetic polymorphisms in the drug metabolizing enzymes and transporters genes among the populations. Here we reviewed the studies of genetic variations in Uyghur Chinese of fifteen CYP450 genes including CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2, CYP2W1, CYP3A4, CYP3A5, CYP4A11, and CYP17A1, which totally covered 277 variants. We also collected the data of 277 variants covered in our study in two extensive population sequencing projects, the International HapMap Project (Hap-Map) and the 1000 Genomes Project and compared them with the data of Uyghur Chinese. The results suggested that remarkable differences of variants allele frequencies of CYP450 genes were existed among Uyghur Chinese and other world populations and drug doses should be adjusted clinically in Uyghur in contrast to Han Chinese and Caucasians.
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Affiliation(s)
- Guangzhao Qi
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Duolu Li
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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16
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Adedeji WA, Igbinoba SI, Fakeye TO, Oladosu IA, Fehintola FA, Ma Q, Morse GD. Evaluation of CYP2D6 phenotype in the Yoruba Nigerian population. Expert Rev Clin Pharmacol 2017; 10:1145-1152. [PMID: 28786716 DOI: 10.1080/17512433.2017.1362979] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND There is a lack of information on CYP2D6, a major metabolizing enzyme, in Africa ethnic nationalities. The objective was to determine CYP2D6 phenotype in Yoruba Nigerians using dextromethorphan (DEX). METHOD A total of 89 healthy volunteers received 30 mg of DEX orally followed by blood and urine sample collection at 3-hour and over 8 h post-dose, respectively. DEX and dextrorphan (DOR) concentrations were determined using High Performance Liquid Chromatography (HPLC). The metabolic ratio (MR, DEX/DOR) were plotted for the phenotype determination. RESULTS The log MR that separated poor (PMs) from normal metabolizers (NMs) was 0.28 and 0.75 for urine and plasma, respectively. Two subjects (2.3%) identified as PMs had a mean MR of 17 and 3.2 in plasma and urine, significantly higher than that of NMs (p < .0001). A positive correlation between urine and plasma MR was noted. CONCLUSION The prevalence of PMs in the Yoruba Nigerians was similar to that reported among blacks.
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Affiliation(s)
- Waheed Adeola Adedeji
- a Department of Clinical Pharmacology , University College Hospital , Ibadan , Nigeria
| | - Sharon Iyobor Igbinoba
- b Department of Clinical Pharmacy & Pharmacy Administration, Faculty of Pharmacy , Obafemi Awolowo University , Ile-Ife , Nigeria
| | - Titilayo O Fakeye
- c Department of Clinical Pharmacy & Pharmacy Administration , University of Ibadan , Ibadan , Nigeria
| | | | - Fatai Adewale Fehintola
- a Department of Clinical Pharmacology , University College Hospital , Ibadan , Nigeria.,e Department of Pharmacology and Therapeutics , University of Ibadan , Ibadan , Nigeria
| | - Qing Ma
- f Translational Pharmacology Research Core , School of Pharmacy and Pharmaceutical Sciences, New York Center of Excellence in Bioinformatics and Life Sciences , Buffalo , NY , USA
| | - Gene D Morse
- f Translational Pharmacology Research Core , School of Pharmacy and Pharmaceutical Sciences, New York Center of Excellence in Bioinformatics and Life Sciences , Buffalo , NY , USA.,g Center for Integrated Global Biomedical Sciences , University at Buffalo , Buffalo , NY , USA
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Anusha A, Narendar D, Krishna Murthy B, Goverdhan P. Influence of Single and Multi Dose Treatment of Glipizide on Pharmacokinetics and Pharmacodynamics of Irbesartan in Normal and Hypertensive Rats. High Blood Press Cardiovasc Prev 2017; 24:179-185. [DOI: 10.1007/s40292-017-0195-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 03/20/2017] [Indexed: 11/28/2022] Open
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Ning J, Louisse J, Spenkelink B, Wesseling S, Rietjens IMCM. Study on inter-ethnic human differences in bioactivation and detoxification of estragole using physiologically based kinetic modeling. Arch Toxicol 2017; 91:3093-3108. [PMID: 28357488 PMCID: PMC5562778 DOI: 10.1007/s00204-017-1941-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 02/21/2017] [Indexed: 12/21/2022]
Abstract
Considering the rapid developments in food safety in the past decade in China, it is of importance to obtain insight into what extent safety and risk assessments of chemicals performed for the Caucasian population apply to the Chinese population. The aim of the present study was to determine physiologically based kinetic (PBK) modeling-based predictions for differences between Chinese and Caucasians in terms of metabolic bioactivation and detoxification of the food-borne genotoxic carcinogen estragole. The PBK models were defined based on kinetic constants for hepatic metabolism derived from in vitro incubations using liver fractions of the two ethnic groups, and used to evaluate the inter-ethnic differences in metabolic activation and detoxification of estragole. The models predicted that at realistic dietary intake levels, only 0.02% of the dose was converted to the ultimate carcinogenic metabolite 1′-sulfooxyestragole in Chinese subjects, whereas this amounted to 0.09% of the dose in Caucasian subjects. Detoxification of 1′-hydroxyestragole, mainly via conversion to 1′-oxoestragole, was similar within the two ethnic groups. The 4.5-fold variation in formation of the ultimate carcinogenic metabolite of estragole accompanied by similar rates of detoxification may indicate a lower risk of estragole for the Chinese population at similar levels of exposure. The study provides a proof of principle for how PBK modeling can identify differences in ethnic sensitivity and provide a more refined risk assessment for a specific ethnic group for a compound of concern.
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Affiliation(s)
- Jia Ning
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands.
| | - Jochem Louisse
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Bert Spenkelink
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Sebastiaan Wesseling
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
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Koukoula M, Dotsikas Y, Molou E, Schulpis KH, Thodi G, Chatzidaki M, Triantafylli O, Loukas YL. Study of the effect of CYP2C19 polymorphisms on omeprazole pharmacokinetics by utilizing validated LC–MS/MS and Real Time-PCR methods. J Chromatogr B Analyt Technol Biomed Life Sci 2017; 1047:173-179. [DOI: 10.1016/j.jchromb.2016.06.046] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 05/08/2016] [Accepted: 06/27/2016] [Indexed: 11/15/2022]
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20
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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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21
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Stephens DB, de Leon J. CYP2D6 ultra-rapid metabolizer phenotype not associated with attempted suicide in a large sample of psychiatric inpatients. Pharmacogenomics 2016; 17:1295-304. [PMID: 27463022 DOI: 10.2217/pgs-2016-0086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIM Suicide accounts for over 800,000 deaths per year worldwide and is the tenth-leading cause of mortality in USA. Several studies have investigated cytochrome P450 CYP2D6 ultra-rapid metabolizer (UM) phenotype in relation to suicidality, with mixed results. This study tested the hypothesis of increased suicide risk among CYP2D6 UMs. PATIENTS & METHODS Among the 4264 state psychiatric hospital inpatients included, 2435 (57%) reported a prior suicide attempt. RESULTS No association between UM status and attempted suicide was observed in bivariate (odds ratio: 0.87; 95% CI: 0.53-1.25), multivariate (adjusted odds ratio: 0.89; 95% CI: 0.55-1.46), or risk-stratified analyses. CONCLUSION These results contrast with prior reports of increased suicidality among CYP2D6 UMs and highlight the pressing need to identify reliable screening methods to better address this persistent public health problem.
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Affiliation(s)
- Dustin B Stephens
- Department of Behavioral Science, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Jose de Leon
- Department of Psychiatry, University of Kentucky College of Medicine, Lexington, KY, USA
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Tverdohleb T, Dinc B, Knezevic I, Candido KD, Knezevic NN. The role of cytochrome P450 pharmacogenomics in chronic non-cancer pain patients. Expert Opin Drug Metab Toxicol 2016; 12:1303-1311. [PMID: 27388970 DOI: 10.1080/17425255.2016.1209482] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Pharmacogenomics is the field that studies an individualized treatment approach for patients' medication regimen that can impact drug safety, productivity, and personalized health care. Pharmacogenomics characterizes the genetic differences in metabolic pathways which can affect a patient's individual responses to drug treatments. Areas covered: The various responses to pharmacological agents are mainly determined by the different types of genetic variants of the CYP450. CYP2D6 polymorphism is well known for its variation in the metabolism of drugs from many therapeutic arenas, including some analgesic drugs such as codeine, hydromorphone, oxycodone and tramadol. Allele combinations determine the phenotypic expression, characterized as either: extensive metabolizer, intermediate metabolizer, ultra-rapid metabolizer and poor metabolizer. Expert opinion: The Human Genome Project (HGP) revolutionized the future of medicine and the way health care providers approach individualized patient treatment, and chronic pain management is one of those areas. The key findings in the literature appear to be related to the CYP2D6 expression and its high polymorphism influencing the metabolism of opioid medications, and the impact of that on the patient's therapeutic outcome thus exemplifying the importance of genetic testing for CYP2D6 in the process of physician therapeutic decision making.
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Affiliation(s)
- Tatiana Tverdohleb
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL , USA
| | - Bora Dinc
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL , USA
| | - Ivana Knezevic
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL , USA
| | - Kenneth D Candido
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL , USA.,b Department of Anesthesiology, College of Medicine , University of Illinois , Chicago , IL , USA.,c Department of Surgery, College of Medicine , University of Illinois , Chicago , IL , USA
| | - Nebojsa Nick Knezevic
- a Department of Anesthesiology , Advocate Illinois Masonic Medical Center , Chicago , IL , USA.,b Department of Anesthesiology, College of Medicine , University of Illinois , Chicago , IL , USA.,c Department of Surgery, College of Medicine , University of Illinois , Chicago , IL , USA
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Amal Al Omari, Murry DJ. Pharmacogenetics of the Cytochrome P450 Enzyme System: Review of Current Knowledge and Clinical Significance. J Pharm Pract 2016. [DOI: 10.1177/0897190007304821] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genetic variation in drug metabolizing enzymes is an important contributor to interindividual variation in drug disposition and response and is associated with significant clinical consequences. Many commonly used drugs are dependent on the cytochrome P450 monooxygenase enzymes (CYP450) for their metabolism and elimination. At present, more than 57 active human CYP450 genes are known, and the majority of these genes are polymorphic. Despite the large number of CYP450 genes, only the CYP1, CYP2, and CYP3 families of enzymes have a major role in drug metabolism. Approximately 10 CYP450s are responsible for the metabolism of a large number of pharmacologic agents in human beings. The polymorphic forms of the CYP450s are responsible for the development of a significant number of adverse drug reactions and may also contribute to drug response. Genetic polymorphisms have now been identified in the genes encoding all the main CYP450s that contribute to drug and other xenobiotic metabolism, and there are marked interethnic differences in the distribution and frequency of variant alleles. A review of the progress in the pharmacogenetics of P450s that are important for drug metabolism is presented with particular emphasis on the clinical relevance of this research.
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Affiliation(s)
- Amal Al Omari
- Department of Clinical and Administrative Pharmacy at the University of Iowa
| | - Daryl J. Murry
- Department of Clinical and Administrative Pharmacy, College of Pharmacy, S418 Phar, University of Iowa, 115 S. Grand Ave, Iowa City, IA 52242,
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24
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Mugoša S, Djordjević N, Djukanović N, Protić D, Bukumirić Z, Radosavljević I, Bošković A, Todorović Z. Factors affecting the development of adverse drug reactions to β-blockers in hospitalized cardiac patient population. Patient Prefer Adherence 2016; 10:1461-9. [PMID: 27536078 PMCID: PMC4977081 DOI: 10.2147/ppa.s108579] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The aim of the present study was to undertake a study on the prevalence of cytochrome P450 2D6 (CYP2D6) poor metabolizer alleles (*3, *4, *5, and *6) on a Montenegrin population and its impact on developing adverse drug reactions (ADRs) of β-blockers in a hospitalized cardiac patient population. A prospective study was conducted in the Cardiology Center of the Clinical Center of Montenegro and included 138 patients who had received any β-blocker in their therapy. ADRs were collected using a specially designed questionnaire, based on the symptom list and any signs that could point to eventual ADRs. Data from patients' medical charts, laboratory tests, and other available parameters were observed and combined with the data from the questionnaire. ADRs to β-blockers were observed in 15 (10.9%) patients. There was a statistically significant difference in the frequency of ADRs in relation to genetically determined enzymatic activity (P<0.001), with ADRs' occurrence significantly correlating with slower CYP2D6 metabolism. Our study showed that the adverse reactions to β-blockers could be predicted by the length of hospitalization, CYP2D6 poor metabolizer phenotype, and the concomitant use of other CYP2D6-metabolizing drugs. Therefore, in hospitalized patients with polypharmacy CYP2D6 genotyping might be useful in detecting those at risk of ADRs.
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Affiliation(s)
- Snežana Mugoša
- Department of Pharmacotherapy, Faculty of Pharmacy, University of Montenegro
- Clinical Trial Department, Agency for Medicines and Medical Devices of Montenegro, Podgorica, Montenegro
| | - Nataša Djordjević
- Department of Pharmacology and Toxicology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac
| | | | - Dragana Protić
- Department of Pharmacology, Clinical Pharmacology and Toxicology
| | - Zoran Bukumirić
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade
| | - Ivan Radosavljević
- Department of Surgery, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Aneta Bošković
- Clinic for Heart Diseases, Clinical Centre of Montenegro, Podgorica, Montenegro
| | - Zoran Todorović
- Department of Pharmacology, Clinical Pharmacology and Toxicology
- Department of Clinical Immunology and Allergy, Medical Center “Bežanijska kosa”, Belgrade, Serbia
- Correspondence: Zoran Todorović, Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Dr Subotića Starijeg 1, PO Box 38, 11129 Belgrade, Serbia, Tel +381 11 36 43 389, Fax +381 11 36 43 397, Email
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25
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Flaten HK, Kim HS, Campbell J, Hamilton L, Monte AA. CYP2C19 drug-drug and drug-gene interactions in ED patients. Am J Emerg Med 2015; 34:245-9. [PMID: 26639454 DOI: 10.1016/j.ajem.2015.10.055] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 10/24/2015] [Accepted: 10/30/2015] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND CYP450 polymorphisms result in variable rates of drug metabolism. CYP drug-drug interactions can contribute to altered drug effectiveness and safety. STUDY OBJECTIVES The primary objective was to determine the percentage of emergency department (ED) patients with cytochrome 2C19 (CYP2C19) drug-drug interactions. The secondary objective was to determine the prevalence of CYP2C19 polymorphisms in a US ED population. METHODS We conducted a prospective observational study in an urban academic ED with 72,000 annual visits. Drug ingestion histories for the 48 hours preceding ED visit were obtained; each drug was coded as CYP2C19 substrate, inhibitor, inducer, or not CYP2C19 dependent. Ten percent of patients were randomized to undergo CYP2C19 genotyping using the Roche Amplichip. RESULTS A total of 502 patients were included; 61% were female, 65% were white, and median age was 39 years (interquartile range, 22-53). One hundred thirty-one (26.1%) patients had taken at least 1 CYP2C19-dependent home drug. Eighteen (13.7%) patients who were already taking a CYP2C19-dependent drug were given or prescribed a CYP2C19-dependent drug while in the ED. Among the 53 patients genotyped, 52 (98%) were extensive metabolizers and 1 was a poor metabolizer. CONCLUSIONS In a population of ED patients, more than a quarter had taken a CYP2C19-dependent drug in the preceding 48 hours, but few were given or prescribed another CYP2C19-dependent drug in the ED. On genotyping analysis, CYP2C19 polymorphisms were uncommon in our cohort. We conclude that changing prescribing practice due to CYP2C19 drug-drug interaction or genotype is unlikely to be useful in most US ED populations.
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Affiliation(s)
- Hanna K Flaten
- University of Colorado Department of Emergency Medicine, 12401 E 17th Ave, Aurora, CO, 80045
| | - Howard S Kim
- Denver Health Residency in Emergency Medicine, 770 Bannock St, Denver, CO, 80204
| | - Jenny Campbell
- University of Colorado Department of Emergency Medicine, 12401 E 17th Ave, Aurora, CO, 80045
| | - Lisa Hamilton
- University of Colorado School of Medicine, 12401 E 17th Ave, Aurora, CO, 80045
| | - Andrew A Monte
- University of Colorado Department of Emergency Medicine, 12401 E 17th Ave, Aurora, CO, 80045; Denver Health Residency in Emergency Medicine, 770 Bannock St, Denver, CO, 80204; University of Colorado School of Medicine, 12401 E 17th Ave, Aurora, CO, 80045; Skaggs School of Pharmacy and Pharmaceutical Sciences, 12401 E 17th Ave, Aurora, CO, 80045; Rocky Mountain Poison & Drug Center, 990 Bannock St, Denver, CO, 80204.
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Chin FW, Chan SC, Abdul Rahman S, Noor Akmal S, Rosli R. CYP2D6 Genetic Polymorphisms and Phenotypes in Different Ethnicities of Malaysian Breast Cancer Patients. Breast J 2015; 22:54-62. [DOI: 10.1111/tbj.12518] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Fee Wai Chin
- Genetic Medicine Research Centre; Faculty of Medicine and Health Sciences; Universiti Putra Malaysia; Serdang Selangor Malaysia
| | - Soon Choy Chan
- Perdana University Graduate School of Medicine (PUGSOM); Serdang Selangor Malaysia
| | - Sabariah Abdul Rahman
- Medical Education Unit; Faculty of Medicine; Universiti Teknologi MARA; Batu Caves Selangor Malaysia
- Laboratory of Medical Sciences; Faculty of Medicine; Universiti Teknologi MARA; Sungai Buloh Selangor Malaysia
| | - Sharifah Noor Akmal
- Department of Pathology; Faculty of Medicine; Universiti Kebangsaan Malaysia Medical Centre; Cheras Kuala Lumpur Malaysia
| | - Rozita Rosli
- Genetic Medicine Research Centre; Faculty of Medicine and Health Sciences; Universiti Putra Malaysia; Serdang Selangor Malaysia
- UPM-MAKNA Cancer Research Laboratory; Institute of Bioscience; Universiti Putra Malaysia; Serdang Selangor Malaysia
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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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Abstract
Practitioners are highly likely to encounter patients with concurrent use of nicotine products and opioid analgesics. Smokers present with more severe and extended chronic pain outcomes and have a higher frequency of prescription opioid use. Current tobacco smoking is a strong predictor of risk for nonmedical use of prescription opioids. Opioid and nicotinic-cholinergic neurotransmitter systems interact in important ways to modulate opioid and nicotine effects: dopamine release induced by nicotine is dependent on facilitation by the opioid system, and the nicotinic-acetylcholine system modulates self-administration of several classes of abused drugs-including opioids. Nicotine can serve as a prime for the use of other drugs, which in the case of the opioid system may be bidirectional. Opioids and compounds in tobacco, including nicotine, are metabolized by the cytochrome P450 enzyme system, but the metabolism of opioids and tobacco products can be complicated. Accordingly, drug interactions are possible but not always clear. Because of these issues, asking about nicotine use in patients taking opioids for pain is recommended. When assessing patient tobacco use, practitioners should also obtain information on products other than cigarettes, such as cigars, pipes, smokeless tobacco, and electronic nicotine delivery systems (ENDS, or e-cigarettes). There are multiple forms of behavioral therapy and pharmacotherapy available to assist patients with smoking cessation, and opioid agonist maintenance and pain clinics represent underutilized opportunities for nicotine intervention programs.
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Georgopoulos SD, Papastergiou V, Karatapanis S. Treatment of Helicobacter Pylori infection: optimization strategies in a high resistance era. Expert Opin Pharmacother 2015; 16:2307-17. [PMID: 26330278 DOI: 10.1517/14656566.2015.1084503] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Treatment of Helicobacter pylori (H. pylori) infection is paramount for the management of prevalent gastrointestinal disorders and in the prevention of gastric cancer. Due to increasing antimicrobial resistance, performance of standard triple therapies has now declined to unacceptably low levels. AREAS COVERED In this article: i) we critically revise optimization tools aiming to improve the outcome of standard treatments; ii) we provide updated evidence on the efficacy and rationale for the use of several non-bismuth quadruple regimens in clinical practice, recommended as preferred empirical therapies in areas of high clarithromycin resistance. EXPERT OPINION Prolonged (14-day) treatment duration may boost the efficacy of standard triple therapy by approximately 5%. Use of a high-dose PPI and/or new-generation PPIs, rabeprazole and esomeprazole, might improve eradication rates, particularly in regions where the CYP2C19 rapid metabolizer phenotype is prevalent. Adjunctive probiotics may be considered to improve treatment tolerability, though more data are required to better define their role in H. pylori eradication. Among non-bismuth quadruple regimens, both concomitant and sequential therapies are appropriate options for high-resistance settings; however, concomitant therapy appears to be less impaired by dual clarithromycin/metronidazole resistance. Hybrid therapy is a promising new alternative which seems not to be inferior to concomitant therapy.
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Affiliation(s)
- Sotirios D Georgopoulos
- a 1 Athens Medical P. Faliron General Hospital, Department of Gastroenterology , 17562 Athens, Greece +306 9 32 35 62 78 ; +302 1 04 11 53 75 ;
| | - Vasilios Papastergiou
- b 2 General Hospital of Rhodes, First Department of Internal Medicine , 85100 Rhodes, Greece
| | - Stylianos Karatapanis
- b 2 General Hospital of Rhodes, First Department of Internal Medicine , 85100 Rhodes, Greece
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Bracchi M, Stuart D, Castles R, Khoo S, Back D, Boffito M. Increasing use of 'party drugs' in people living with HIV on antiretrovirals: a concern for patient safety. AIDS 2015; 29:1585-92. [PMID: 26372268 DOI: 10.1097/qad.0000000000000786] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Use of 'party drugs', a particular set of recreational drugs used in the context of 'ChemSex', is frequent among MSM living with HIV. A recently published observational study showed that more than half of HIV-infected MSM interviewed reported use of illicit substances in the previous 3 months, with frequent concomitant use of three or more drugs. These substances are a combination of 'club drugs' (methylenedioxymethamphetamine, gamma-hydroxybutyrate, ketamine, benzodiazepine) and drugs that are more specifically used in a sexualized context (methamphetamine, mephedrone, poppers and erectile dysfunction agents). Although formal data on pharmacokinetic or pharmacodynamic interactions between recreational drugs and antiretroviral agents are lacking, information regarding potentially toxic interactions can be theorized or sometimes conclusions may be drawn from case studies and cohort observational studies. However, the risk of coadministering party drugs and antiretrovirals should not be overestimated. The major risk for a drug-drug interaction is when using ritonavir-boosting or cobicistat-boosting agents, and maybe some nonnucleoside reverse transcriptase inhibitors. Knowledge of the metabolic pathways of 'party drugs' may help in advising patients on which illicit substances have a high potential for drug-drug interactions, as this is not the case for all.
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Affiliation(s)
- Margherita Bracchi
- aSt Stephen's AIDS Trust bDean Street Clinic, Chelsea and Westminster Hospital cJonathan Mann Clinic, Homerton Hospital dUniversity of Liverpool, Liverpool eImperial College, London, UK
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Mittal B, Tulsyan S, Kumar S, Mittal RD, Agarwal G. Cytochrome P450 in Cancer Susceptibility and Treatment. Adv Clin Chem 2015; 71:77-139. [PMID: 26411412 DOI: 10.1016/bs.acc.2015.06.003] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cytochrome 450 (CYP450) designates a group of enzymes abundant in smooth endoplasmic reticulum of hepatocytes and epithelial cells of small intestines. The main function of CYP450 is oxidative catalysis of various endogenous and exogenous substances. CYP450 are implicated in phase I metabolism of 80% of drugs currently in use, including anticancer drugs. They are also involved in synthesis of various hormones and influence hormone-related cancers. CYP450 genes are highly polymorphic and their variants play an important role in cancer risk and treatment. Association studies and meta-analyses have been performed to decipher the role of CYP450 polymorphisms in cancer susceptibility. Cancer treatment involves multimodal therapies and evaluation of CYP450 polymorphisms is necessary for pharmacogenetic assessment of anticancer therapy outcomes. In addition, CYP450 inhibitors are being evaluated for improved pharmacokinetics and oral formulation of several anticancer drugs.
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Affiliation(s)
- Balraj Mittal
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
| | - Sonam Tulsyan
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Surendra Kumar
- Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Rama Devi Mittal
- Department of Urology and Renal Transplant, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Gaurav Agarwal
- Department of Endocrine Surgery, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
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Steere B, Baker JAR, Hall SD, Guo Y. Prediction of in vivo clearance and associated variability of CYP2C19 substrates by genotypes in populations utilizing a pharmacogenetics-based mechanistic model. Drug Metab Dispos 2015; 43:870-83. [PMID: 25845826 DOI: 10.1124/dmd.114.061523] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 04/06/2015] [Indexed: 12/18/2022] Open
Abstract
It is important to examine the cytochrome P450 2C19 (CYP2C19) genetic contribution to drug disposition and responses of CYP2C19 substrates during drug development. Design of such clinical trials requires projection of genotype-dependent in vivo clearance and associated variabilities of the investigational drug, which is not generally available during early stages of drug development, but is essential for CYP2C19 substrates with multiple clearance pathways. This study evaluated the utility of pharmacogenetics-based mechanistic modeling in predicting such parameters. Hepatic CYP2C19 activity and variability within genotypes were derived from in vitro S-mephenytoin metabolic activity in genotyped human liver microsomes (N = 128). These data were then used in mechanistic models to predict genotype-dependent disposition of CYP2C19 substrates (i.e., S-mephenytoin, citalopram, pantoprazole, and voriconazole) by incorporating in vivo clearance or pharmacokinetics of wild-type subjects and parameters of other clearance pathways. Relative to the wild-type, the CYP2C19 abundance (coefficient of variation percentage) in CYP2C19*17/*17, *1/*17, *1/*1, *17/null, *1/null, and null/null microsomes was estimated as 1.85 (117%), 1.79 (155%), 1.00 (138%), 0.83 (80%), 0.38 (130%), and 0 (0%), respectively. The subsequent modeling and simulations predicted, within 2-fold of the observed, the means and variabilities of urinary S/R-mephenytoin ratio (36 of 37 genetic groups), the oral clearance of citalopram (9 of 9 genetic groups) and pantoprazole (6 of 6 genetic groups), and voriconazole oral clearance (4 of 4 genetic groups). Thus, relative CYP2C19 genotype-dependent hepatic activity and variability were quantified in vitro and used in a mechanistic model to predict pharmacokinetic variability, thus allowing the design of pharmacogenetics and drug-drug interaction trials for CYP2C19 substrates.
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Affiliation(s)
- Boyd Steere
- Research IT Informatics (B.S.), Clinical Diagnostic Laboratory (J.A.R.B.), and Drug Disposition (S.D.H., Y.G.), Eli Lilly and Company, Indianapolis, Indiana
| | - Jessica A Roseberry Baker
- Research IT Informatics (B.S.), Clinical Diagnostic Laboratory (J.A.R.B.), and Drug Disposition (S.D.H., Y.G.), Eli Lilly and Company, Indianapolis, Indiana
| | - Stephen D Hall
- Research IT Informatics (B.S.), Clinical Diagnostic Laboratory (J.A.R.B.), and Drug Disposition (S.D.H., Y.G.), Eli Lilly and Company, Indianapolis, Indiana
| | - Yingying Guo
- Research IT Informatics (B.S.), Clinical Diagnostic Laboratory (J.A.R.B.), and Drug Disposition (S.D.H., Y.G.), Eli Lilly and Company, Indianapolis, Indiana
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Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol 2015; 71:549-67. [PMID: 25870032 PMCID: PMC4412688 DOI: 10.1007/s00228-015-1832-0] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/04/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE The therapeutic index (TI) is the range of doses at which a medication is effective without unacceptable adverse events. Drugs with a narrow TI (NTIDs) have a narrow window between their effective doses and those at which they produce adverse toxic effects. Generic drugs may be substituted for brand-name drugs provided that they meet the recommended bioequivalence (BE) limits. However, an appropriate range of BE for NTIDs is essential to define due to the potential for ineffectiveness or adverse events. Flecainide is an antiarrhythmic agent that has the potential to be considered an NTID. This review aims to evaluate the literature surrounding guidelines on generic substitution for NTIDs and to evaluate the evidence for flecainide to be considered an NTID. METHODS A review of recommendations from various regulatory authorities regarding BE and NTIDs, and publications regarding the NTID characteristics of flecainide, was carried out. RESULTS Regulatory authorities generally recommend reduced BE limits for NTIDs. Some, but not all, regulatory authorities specify flecainide as an NTID. The literature review demonstrated that flecainide displays NTID characteristics including a steep drug dose-response relationship for safety and efficacy, a need for therapeutic drug monitoring of pharmacokinetic (PK) or pharmacodynamics measures and intra-subject variability in its PK properties. CONCLUSIONS There is much evidence for flecainide to be considered an NTID based on both preclinical and clinical data. A clear understanding of the potential of proarrhythmic effects or lack of efficacy, careful patient selection and regular monitoring are essential for the safe and rational administration of flecainide.
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Affiliation(s)
- Juan Tamargo
- Department of Pharmacology, School of Medicine, University Complutense, 28040, Madrid, Spain,
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Abstract
Clinicians already face "personalized" medicine every day while experiencing the great variation in toxicities and drug efficacy among individual patients. Pharmacogenetics studies are the platform for discovering the DNA determinants of variability in drug response and tolerability. Research now focuses on the genome after its beginning with analyses of single genes. Therapeutic outcomes from several psychotropic drugs have been weakly linked to specific genetic variants without independent replication. Drug side effects show stronger associations to genetic variants, including human leukocyte antigen loci with carbamazepine-induced dermatologic outcome and MC4R with atypical antipsychotic weight gain. Clinical implementation has proven challenging, with barriers including a lack of replicable prospective evidence for clinical utility required for altering medical care. More recent studies show promising approaches for reducing these barriers to routine incorporation of pharmacogenetics data into clinical care.
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Ballas SK. Pathophysiology and principles of management of the many faces of the acute vaso-occlusive crisis in patients with sickle cell disease. Eur J Haematol 2014; 95:113-23. [PMID: 25288149 DOI: 10.1111/ejh.12460] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2014] [Indexed: 12/11/2022]
Abstract
Effective management of sickle cell pain entails a thorough understanding of its pathophysiology and the pharmacogenomics of the opioids used to manage it. In recent years, there has been significant progress along these two lines. At the pathophysiologic level, there is evidence that the severity and frequency of painful stimuli modulate their transmission at the level of the dorsal horn of the spinal cord. This modulation is achieved via two channels: the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors. Initially, the AMPA channel controls the transmission of stimuli of mild-moderate severity. Once the AMPA channel reaches its limit of membrane depolarization, the NMDA channel is activated and facilitates the transmission of painful stimuli in a progressive fashion leading to central sensitization and glial activation. At the level of pharmacogenomics, the metabolism of each opioid is patient-specific. Glucuronidation is unique for the metabolism of morphine, hydromorphone, and oxymorphone. The metabolism of all other opioids requires specific Cytochrome P450 (CYP) isoenzymes. The activity of each isoenzyme and the activity of the metabolites of each opioid vary among patients depending on their genetic makeup and coexistent environmental factors such as the use of other medications that may enhance or inhibit the CYP isoenzyme activity.
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Affiliation(s)
- Samir K Ballas
- Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA, USA
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Cho DY, Bae SH, Lee JK, Park JB, Kim YW, Lee S, Oh E, Kim BT, Bae SK. Effect of the potent CYP2D6 inhibitor sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy male Korean volunteers. Xenobiotica 2014; 45:256-63. [PMID: 25268386 DOI: 10.3109/00498254.2014.967824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. Recently, we demonstrated that sarpogrelate is a potent and selective CYP2D6 inhibitor in vitro. Here, we evaluated the effect of sarpogrelate on the pharmacokinetics and pharmacodynamics of metoprolol in healthy subjects. 2. Nine healthy male subjects genotyped for CYP2D6*1/*1 or *1/*2 were included in an open-label, randomized, three treatment-period and crossover study. A single oral dose of metoprolol (100 mg) was administered with water (treatment A) and sarpogrelate (100 mg bid.; a total dose of 200 mg and treatment B), or after pretreatment of sarpogrelate for three days (100 mg tid.; treatment C). Plasma levels of metoprolol and α-hydroxymetoprolol were determined using a validated LC-MS/MS method. Changes in heart rate and blood pressure were monitored as pharmacodynamic responses to metoprolol. 3. Metoprolol was well tolerated in the three treatment groups. In treatment B and C groups, the AUCt of metoprolol increased by 53% (GMR, 1.53; 90% CI, 1.17-2.31) and by 51% (1.51; 1.17-2.31), respectively. Similar patterns were observed for the increase in Cmax of metoprolol by sarpogrelate. However, the pharmacodynamics of metoprolol did not differ significantly among the three treatment groups. 4. Greater systemic exposure to metoprolol after co-administration or pretreatment with sarpogrelate did not result in clinically relevant effects. Co-administration of both agents is well tolerated and can be employed without the need for dose adjustments.
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Affiliation(s)
- Doo-Yeoun Cho
- Department of Family Practice and Community Health, Ajou University School of Medicine , Yeongtong-gu, Suwon , South Korea
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Sosa-Macías M, Llerena A. Cytochrome P450 genetic polymorphisms of Mexican indigenous populations. ACTA ACUST UNITED AC 2014; 28:193-208. [PMID: 24145057 DOI: 10.1515/dmdi-2013-0037] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/02/2013] [Indexed: 11/15/2022]
Abstract
This review focuses on the genetic polymorphisms of the cytochrome P450 (CYP) genes in Mexican indigenous populations, who are a part of the wide ethnic diversity of this country. These native groups have a particular historical trajectory that is different from the Mexican Mestizos. This variability may be reflected in the frequency distribution of polymorphisms in the CYP genes that encode enzymes involved in the metabolism of drugs and other xenobiotics. Therefore, these polymorphisms may affect drug efficacy and safety in indigenous populations in Mexico. The present study aimed to analyze the prevalence of CYP polymorphisms in indigenous Mexicans and to compare the results with studies in Mexican Mestizos. Because the extrapolation of pharmacogenetic data from Mestizos is not applicable to the majority of indigenous groups, pharmacogenetic studies directed at indigenous populations need to be developed. The Amerindians analyzed in this study showed a low phenotypic (CYP2D6) and genotypic (CYP2D6, CYP2C9) diversity, unlike Mexican Mestizos. The frequency of polymorphisms in the CYP1A1, CYP2C19, CYP2E1, and CYP3A4 genes was more similar among the Amerindians and Mexican Mestizos, with the exception of the CYP1A2 gene, whose *1F variant frequency in Mexican Amerindians was the highest described to date.
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Li X, Suhar T, Glass L, Rajaraman G. A High-Throughput (HTS) Assay for Enzyme Reaction Phenotyping in Human Recombinant P450 Enzymes Using LC-MS/MS. CURRENT PROTOCOLS IN PHARMACOLOGY 2014; 64:9.18.1-9.18.10. [PMID: 26344210 DOI: 10.1002/0471141755.ph0918s64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Enzyme reaction phenotyping is employed extensively during the early stages of drug discovery to identify the enzymes responsible for the metabolism of new chemical entities (NCEs). Early identification of metabolic pathways facilitates prediction of potential drug-drug interactions associated with enzyme polymorphism, induction, or inhibition, and aids in the design of clinical trials. Incubation of NCEs with human recombinant enzymes is a popular method for such work because of the specificity, simplicity, and high-throughput nature of this approach for phenotyping studies. The availability of a relative abundance factor and calculated intersystem extrapolation factor for the expressed recombinant enzymes facilitates easy scaling of in vitro data, enabling in vitro-in vivo extrapolation. Described in this unit is a high-throughput screen for identifying enzymes involved in the metabolism of NCEs. Emphasis is placed on the analysis of the human recombinant enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2B6, and CYP3A4, including the calculation of the intrinsic clearance for each.
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Affiliation(s)
- Xiaofeng Li
- AbbVie, Drug Metabolism, North Chicago, Illinois
| | - Tom Suhar
- AbbVie, Drug Metabolism, North Chicago, Illinois
| | - Lateca Glass
- AbbVie, Drug Metabolism, North Chicago, Illinois
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A systematically combined genotype and functional combination analysis of CYP2E1, CYP2D6, CYP2C9, CYP2C19 in different geographic areas of mainland China--a basis for personalized therapy. PLoS One 2013; 8:e71934. [PMID: 24098323 PMCID: PMC3788764 DOI: 10.1371/journal.pone.0071934] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 07/05/2013] [Indexed: 11/20/2022] Open
Abstract
The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes—CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.
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Polymorphisms and phenotypic analysis of cytochrome P450 2D6 in the Tibetan population. Gene 2013; 527:360-5. [DOI: 10.1016/j.gene.2013.03.110] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Revised: 03/20/2013] [Accepted: 03/25/2013] [Indexed: 11/22/2022]
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Bruckenthal P, Barkin RL. Options for treating postherpetic neuralgia in the medically complicated patient. Ther Clin Risk Manag 2013; 9:329-40. [PMID: 23990726 PMCID: PMC3753169 DOI: 10.2147/tcrm.s47138] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Patients with postherpetic neuralgia (PHN) are often of advanced age or immunocompromised and likely to have ≥1 comorbid medical condition for which they receive ≥1 medication (polypharmacy). Comorbidities affecting renal or hepatic function can alter pharmacokinetics, thereby impacting the efficacy or tolerability of PHN analgesic therapies. Cardiovascular, cerebrovascular, or psychiatric comorbidities may increase patient vulnerability to potential adverse events associated with some PHN analgesic therapies. Because PHN is a localized condition, localized therapy with a topical analgesic (lidocaine patch 5% and capsaicin 8% patch or cream) may provide adequate efficacy while mitigating the risk of systemic adverse events compared with oral analgesics (eg, tricyclic antidepressants, anticonvulsants, opioids). However, combined therapy with a topical and an oral analgesic or with >1 oral analgesic may be needed for optimal pain management in some patients. This review summarizes how comorbidities and concomitant medications should be taken into account when selecting among available pharmacotherapies for PHN and provides recommendations for the selection of therapies that will provide analgesia while minimizing the risk of adverse events.
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Affiliation(s)
- Patricia Bruckenthal
- Department of Graduate Studies in Advanced Practice Nursing, Stony Brook University School of Nursing, Stony Brook, NY, USA
| | - Robert L Barkin
- Department of Anesthesiology, Family Medicine, and Pharmacology, Rush University Medical College, Chicago, IL, USA
- Department of Anesthesiology, Northshore University Health System Pain Centers, Skokie and Evanston Hospitals, Skokie and Evanston, IL, USA
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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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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: 24] [Impact Index Per Article: 2.0] [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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Liu J, Shentu JZ, Wu LH, Dou J, Xu QY, Zhou HL, Wu GL, Huang MZ, Hu XJ, Chen JC. Relative bioavailability and pharmacokinetic comparison of two different enteric formulations of omeprazole. J Zhejiang Univ Sci B 2012; 13:348-55. [PMID: 22556172 DOI: 10.1631/jzus.b1100272] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
In order to comply with the requirements for a drug listed in China, the study was developed to compare the pharmacokinetics and relative bioavailability of two different enteric formulations of omeprazole (OPZ) in healthy Chinese subjects. A total of 32 volunteers participated in the study. Plasma concentrations were analyzed by nonstereospecific liquid chromatography/tandem mass spectrometric (LC-MS/MS) method. After administration of a single 40-mg dose of the two OPZ formulations, the comparative bioavailability was assessed by calculating individual AUC(0‒t) (the area under the concentration-time curve from time zero to the last measurable concentration), AUC(0‒∞) (the area under the concentration-time curve extrapolated to infinity), C(max) (the maximum observed concentration), and T(peak) (the time to C(max)) values of OPZ, 5-hydroxyomeprazole (OH-OPZ), and omeprazole sulfone (OPZ-SFN), respectively. The 90% confidence intervals (CIs) of AUC(0‒t), AUC(0‒∞), and C(max) were 85.4%‒99.0%/88.8%‒98.6%/87.6%‒99.4%, 85.5%‒99.2%/89.0%‒98.6%/88.5%‒101.3%, and 72.3%‒87.6%/79.6%‒91.1%/88.4%‒99.1% for OPZ/OH-OPZ/OPZ-SFN, respectively, and T(peak) values did not differ significantly. In this study, the test formulation of OPZ in fasting healthy Chinese male volunteers met the Chinese bioequivalance standard to the reference formulation based on AUC, C(max), and T(peak).
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Affiliation(s)
- Jian Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Infectious Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing. Eur J Drug Metab Pharmacokinet 2012; 38:43-51. [DOI: 10.1007/s13318-012-0100-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 06/25/2012] [Indexed: 10/27/2022]
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Noubarani M, Kobarfard F, Motevalian M, Keyhanfar F. Variation in omeprazole pharmacokinetics in a random Iranian population: a pilot study. Biopharm Drug Dispos 2012; 33:324-31. [PMID: 22890488 DOI: 10.1002/bdd.1805] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Omeprazole is metabolized in the liver mainly by the polymorphic CYP2C19 enzyme. Considerable ethnic differences have been reported in the pharmacokinetics of omeprazole. The present study was conducted to evaluate the pharmacokinetic parameters of omeprazole after a single oral administration to a random Iranian population. Thirty healthy male subjects, aged 24-31 years, weighing 60-98 kg completed the study. Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 20 mg omeprazole. The pharmacokinetic parameters were calculated from the plasma concentration-time profiles. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was used to quantify 5-hydroxyomeprazole. The mean area under the concentration-time curve (AUC) from time zero to infinity (AUC(∞) ) values of omeprazole and the corresponding coefficient of variation (CV%) was 987.3 ng h/ml (65%). In general, most subjects showed a normal distribution. Only one subject showed a very high AUC compared with the corresponding mean AUC level. This subject had the highest half-life and the lowest rate of elimination. The omeprazole metabolic ratio for this subject was 2.9, while for the others it was in the range 0.12-0.56. These results are consistent with previous literature that showed the existence of interindividual variability in omeprazole pharmacokinetics, even within a single ethnic group. Differences in the pharmacokinetics could be due to differences in the genetic make-up of subjects as found in their omeprazole metabolic ratios.
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Affiliation(s)
- Maryam Noubarani
- Department of Pharmacology and Toxicology, Zanjan University of Medical Sciences, Zanjan, Iran
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Huber-Wechselberger AE, Niedetzky P, Aigner I, Haschke-Becher E. Impact of CYP2D6 polymorphism on tamoxifen therapy: where are we? Wien Med Wochenschr 2012; 162:252-61. [PMID: 22688624 DOI: 10.1007/s10354-012-0118-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Accepted: 03/20/2012] [Indexed: 01/06/2023]
Abstract
Tamoxifen is a mainstay in the treatment of hormone-receptor sensitive breast cancer. To be effective, it needs conversion into 4-hydroxy-tamoxifen and endoxifen. The key enzyme involved is encoded by the gene CYP2D6 of which several, sometimes population-specific alleles are known. Corresponding enzyme variants may result in poor, intermediate, and extensive metabolization and therefore different steady-state plasma levels of active metabolites. Those are hypothesized to be linked to clinical outcomes of tamoxifen therapy. However, a wealth of mostly retrospective cohort studies came up with conflicting results. Appraisal of these studies is difficult and a metaanalysis impossible due to heterogeneity of patient populations, disease factors, treatment modalities, and measured outcomes. As standardization would not overcome intrinsic limitations of retrospective analyses, prospective trials comparing genotype-guided versus unsighted tamoxifen treatment are required to prove whether routine CYP2D6 genotyping is clinically effective and cost-effective.
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Affiliation(s)
- Ariana E Huber-Wechselberger
- Competence Center of Molecular Biology and Genetics, Elisabethinen Hospital Linz GmbH, Fadingerstrasse 1, 4020, Linz, Austria.
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