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1
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Zhang Y, Wang Z, Wang Y, Jin W, Zhang Z, Jin L, Qian J, Zheng L. CYP3A4 and CYP3A5: the crucial roles in clinical drug metabolism and the significant implications of genetic polymorphisms. PeerJ 2024; 12:e18636. [PMID: 39650550 PMCID: PMC11625447 DOI: 10.7717/peerj.18636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 11/12/2024] [Indexed: 12/11/2024] Open
Abstract
CYP3A, a key member of the cytochrome P450 (CYP450) superfamily, is integral to drug metabolism, processing a substantial portion of medications. Their role in drug metabolism is particularly prominent, as CYP3A4 and CYP3A5 metabolize approximately 30-50% of known drugs. The genetic polymorphism of CYP3A4/5 is significant inter-individual variability in enzymatic activity, which can result in different pharmacokinetic profiles in response to the same drug among individuals. These polymorphisms can lead to either increased drug toxicity or reduced therapeutic effects, requiring dosage adjustments based on genetic profiles. Consequently, the study of the enzymatic activity of CYP3A4/5 gene variants is of great importance for the formulation of personalized treatment regimens. This article first reviews the role of CYP3A4/5 in drug metabolism in the human body, including inhibitors and inducers of CYP3A4/5 and drug-drug interactions. In terms of genetic polymorphism, it discusses the detection methods, enzymatic kinetic characteristics, and clinical guidelines for CYP3A5. Finally, the article summarizes the importance of CYP3A4/5 in clinical applications, including personalized therapy, management of drug-drug interactions, and adjustment of drug doses. This review contributes to the understanding of the functions and genetic characteristics of CYP3A4/5, allowing for more effective clinical outcomes through optimized drug therapy.
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Affiliation(s)
- Yuqing Zhang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ziying Wang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yuchao Wang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Weikai Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zheyan Zhang
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lehao Jin
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianchang Qian
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Molecular Toxicology and Pharmacology, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Long Zheng
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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2
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Alsaeed A, Alhaddad MJ, AlKhalaf AA, Alkhudair A, Alqannas N. Successful Treatment of Infective Endocarditis With Oral Antibiotics: A Case Report. Cureus 2023; 15:e43514. [PMID: 37719561 PMCID: PMC10500962 DOI: 10.7759/cureus.43514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/14/2023] [Indexed: 09/19/2023] Open
Abstract
Infective endocarditis (IE) is a serious and potentially life-threatening infection of the heart valves. It is commonly treated with prolonged courses of intravenous antibiotics, and in some cases, surgical intervention may also be necessary. While the use of oral antibiotics in the treatment of IE is generally limited, there are select cases where they may be considered as an alternative treatment option. Here, we report a case of staphylococcal right-sided IE successfully treated with oral antibiotics (linezolid and rifampicin). Our case highlights the potential for oral antibiotics to be used as step-down therapy for select patients with IE.
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Affiliation(s)
- Ali Alsaeed
- Infectious Disease, Dammam Medical Complex, Dammam, SAU
| | | | | | - Ashraf Alkhudair
- Saud Albabtain Cardiac Center, Dammam Medical Complex, Dammam, SAU
| | - Naif Alqannas
- Saud Albabtain Cardiac Center, Dammam Medical Complex, Dammam, SAU
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3
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Hwang KW, Choi JH, Lee SY, Lee SH, Chon MK, Lee J, Kim H, Kim YG, Choi HO, Kim JS, Park YH, Kim JH, Chun KJ, Nam GB, Choi KJ. Oral anticoagulants and concurrent rifampin administration in tuberculosis patients with non-valvular atrial fibrillation. BMC Cardiovasc Disord 2023; 23:182. [PMID: 37016321 PMCID: PMC10074893 DOI: 10.1186/s12872-023-03212-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 03/29/2023] [Indexed: 04/06/2023] Open
Abstract
BACKGROUND Evidence and guidelines for Non-vitamin K antagonist oral anticoagulants (NOACs) use when prescribing concurrent rifampin for tuberculosis treatment in patients with non-valvular atrial fibrillation (NVAF) are limited. METHODS Using the Korean National Health Insurance Service database from January 2009 to December 2018, we performed a population-based retrospective cohort study to assess the net adverse clinical events (NACE), a composite of ischemic stroke or systemic embolism and major bleeding, of NOACs compared with warfarin among NVAF patients taking concurrent rifampin administration for tuberculosis treatment. After a propensity matching score (PSM) analysis, Cox proportional hazards regression was performed in matched cohorts to investigate the clinical outcomes. RESULTS Of the 735 consecutive patients selected, 465 (63.3%) received warfarin and 270 (36.7%) received NOACs. Among 254 pairs of patients after PSM, the crude incidence rate of NACE was 25.6 in NOAC group and 32.8 per 100 person-years in warfarin group. There was no significant difference between NOAC and warfarin use in NACE (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.48-1.14; P = 0.172). Major bleeding was the main driver of NACE, and NOAC use was associated with a statistically significantly lower risk of major bleeding than that with warfarin use (HR, 0.63; 95% CI, 0.40-1.00; P = 0.0499). CONCLUSIONS In our population-based study, there was no statically significant difference in the occurrence of NACE between NOAC and warfarin use. NOAC use may be associated with a lower risk of major bleeding than that with warfarin use.
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Affiliation(s)
- Ki Won Hwang
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea.
| | - Jin Hee Choi
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Soo Yong Lee
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Sang Hyun Lee
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Min Ku Chon
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Jungkuk Lee
- Data Science Team, Hanmi Pharm. Co., Ltd, Seoul, Republic of Korea
| | - Hasung Kim
- Data Science Team, Hanmi Pharm. Co., Ltd, Seoul, Republic of Korea
| | - Yong-Giun Kim
- Division of Cardiology, Department of Internal Medicine, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Hyung Oh Choi
- Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Hospital, Bucheon, Gyeonggi-do, Republic of Korea
| | - Jeong Su Kim
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Yong-Hyun Park
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - June Hong Kim
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Kook Jin Chun
- Division of Cardiology, Department of Internal Medicine, School of Medicine, Pusan National University, Pusan National University Yangsan Hospital, 20, Geumo-ro, Mulgeum-eup, Yangsan, Gyeongnam, 626-770, South Korea
| | - Gi-Byoung Nam
- Heart Institute, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Kee-Joon Choi
- Heart Institute, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
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4
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Salem M, El-Bardissy A, Elshafei MN, Khalil A, Mahmoud H, Fahmi AM, Kasem M, Bader L, Sherbash M, Elawady MI, Abdalazim W, Howady F, Elewa H. Warfarin-Rifampin-Gene (WARIF-G) Interaction: A Retrospective, Genetic, Case-Control Study. Clin Pharmacol Ther 2023; 113:1150-1159. [PMID: 36789833 DOI: 10.1002/cpt.2871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/05/2023] [Indexed: 02/16/2023]
Abstract
Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. Although, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last 50 years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar. We identified and included 36 patients: 22 responders and 14 nonresponders. Warfarin-responders were significantly more likely to have one or more warfarin-sensitizing CYP2C9/VKORC1 alleles than nonresponders (odds ratio = 23.2, 95% confidence interval = 3.2-195.6; P = 0.0001). The mean genetic-based pre-interaction calculated dose was significantly lower for responders than for nonresponders (P < 0.001); and was negatively correlated with warfarin sensitivity index (WSI) (r = -0.58; P = 0.0002). The median percentage time in therapeutic range and mean WSI were significantly higher in the warfarin-sensitizing CYP2C9/VKORC1 alleles carriers than noncarriers (P = 0.017 and 0.0004, respectively). Whereas the warfarin-sensitizing CYP2C9/VKORC1 genotypes were associated with modest on-rifampin warfarin dose requirements, the noncarriers would have required more than double these doses to respond. Warfarin-sensitizing CYP2C9/VKORC1 genotypes and low genetic-based warfarin calculated doses were associated with higher warfarin sensitivity and better anticoagulation quality in patients receiving rifampin concomitantly.
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Affiliation(s)
- Muhammad Salem
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | - Ahmed El-Bardissy
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | | | - Ahmed Khalil
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | - Hesham Mahmoud
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | - Amr Mohamed Fahmi
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar.,College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Mohamed Kasem
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar
| | - Loulia Bader
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Mohamed Sherbash
- Clinical Pharmacy Department, Hamad Medical Corporation, Doha, Qatar.,College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | | | - Walaa Abdalazim
- Infectious Diseases Department, Hamad Medical Corporation, Doha, Qatar
| | - Faraj Howady
- Infectious Diseases Department, Hamad Medical Corporation, Doha, Qatar
| | - Hazem Elewa
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
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5
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Alnewais ME, Landolfa SL, Bean M, Fermo JD. Successful Anticoagulation With Warfarin After Switching From Rifampin to Rifabutin. J Prim Care Community Health 2023; 14:21501319231197588. [PMID: 37750044 PMCID: PMC10521264 DOI: 10.1177/21501319231197588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 08/04/2023] [Accepted: 08/10/2023] [Indexed: 09/27/2023] Open
Abstract
PURPOSE A case of a patient receiving warfarin for pulmonary embolism (PE) concomitantly with rifampin for treatment of active pulmonary tuberculosis (PTB) is presented. A successful clinical intervention whereby the patient achieved therapeutic anticoagulation after switching to an alternative rifamycin antibacterial, rifabutin, is described. SUMMARY The drug-drug interaction between warfarin and rifampin is well known and documented. However, to our knowledge, no case reports of the interaction between warfarin and rifabutin have been published, and literature describing this interaction is lacking. We describe the case of a 27-year-old African American female referred to a pharmacist-managed anticoagulation clinic for treatment of PE with warfarin. The patient was also being treated for active tuberculosis with rifampin, isoniazid, pyrazinamide, and ethambutol. Warfarin was initiated and over the course of 1 month was continuously increased to a total weekly dose (TWD) of 140 mg without ever achieving the target international normalized ratio (INR) of 2 to 3. In an attempt to reach the target INR, rifampin was switched to rifabutin to minimize the drug-drug interaction with warfarin. Six days after this switch, the target INR was achieved with a lower warfarin TWD of 115 mg. Rifabutin interacts with warfarin to a lesser degree than rifampin and may be considered as an alternative in patients taking warfarin who require treatment with a rifamycin. CONCLUSION For patients in whom therapeutic anticoagulation with warfarin has been difficult, the use of rifabutin may be considered in place of rifampin when the concomitant use of a rifamycin is required.
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Affiliation(s)
- Marwah E. Alnewais
- King Faisal University, Alahsa, Saudi Arabia
- Boston Medical Center, Boston, MA, USA
| | | | | | - Joli D. Fermo
- Medical University of South Carolina, Charleston, SC, USA
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6
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MacDougall C, Canonica T, Keh C, P. Phan BA, Louie J. Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management. Pharmacotherapy 2022; 42:343-361. [DOI: 10.1002/phar.2672] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/04/2022] [Accepted: 02/07/2022] [Indexed: 02/01/2023]
Affiliation(s)
- Conan MacDougall
- Department of Clinical Pharmacy University of California San Francisco School of Pharmacy San Francisco California USA
| | - Theora Canonica
- Department of Clinical Pharmacy San Francisco Veterans' Affairs Medical Center San Francisco California USA
| | - Chris Keh
- Division of Infectious Disease University of California, San Francisco San Francisco California USA
| | - Binh An P. Phan
- Division of Cardiology San Francisco General Hospital University of California, San Francisco San Francisco California USA
| | - Janice Louie
- Division of Infectious Diseases San Francisco Department of Public Health Tuberculosis Clinic University of California, San Francisco San Francisco California USA
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7
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Hu YN, Zhou BT, Yang HR, Peng QL, Gu XR, Sun SS. Effect of rifampicin on anticoagulation of warfarin: A case report. World J Clin Cases 2021; 9:1087-1095. [PMID: 33644171 PMCID: PMC7896655 DOI: 10.12998/wjcc.v9.i5.1087] [Citation(s) in RCA: 4] [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: 06/09/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The drug interaction between warfarin and rifampicin is widely known, but there are still some difficulties in managing the combination of the two drugs.
CASE SUMMARY A patient with brucellosis received strict monitoring from a Chinese pharmacist team during combination of warfarin and rifampicin. The dose of warfarin was increased to 350% in 3 mo before reaching the lower international normalized ratio treatment window. No obvious adverse reaction occurred during the drug-adjustment period. This is the first case report of long-term combined use of rifampicin and warfarin in patients with brucellosis and valve replacement in China based on the Chinese lower warfarin dose and international normalized ratio range.
CONCLUSION Anticoagulation for valve replacement in Chinese patients differs from that in other races. Establishment of a pharmacist clinic provides vital assistance in warfarin dose adjustment.
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Affiliation(s)
- Ya-Ni Hu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Bo-Ting Zhou
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
- The Institute of Hospital Pharmacy, Central South University, Changsha 410008, Hunan Province, China
| | - Hua-Rong Yang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Qi-Lin Peng
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Xu-Rui Gu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan Province, China
| | - Shu-Sen Sun
- College of Pharmacy and Health Sciences, Western New England University, Springfield, MA 31329, United States
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8
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Salem M, Eljilany I, El-Bardissy A, Elewa H. Genetic Polymorphism Effect on Warfarin-Rifampin Interaction: A Case Report and Review of Literature. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:149-156. [PMID: 33542643 PMCID: PMC7851577 DOI: 10.2147/pgpm.s288918] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/29/2020] [Indexed: 01/06/2023]
Abstract
Warfarin-rifampin interaction has been reported since the 1970s. Due to rifampin's strong induction of CYP2C9, most cases could not attain the target international normalized ratio (INR) despite warfarin dose escalation. Genetic polymorphisms determine up to 50% of warfarin dose variability. A 38-year-old woman was started on warfarin and rifampin for cerebral venous sinus thrombosis and pulmonary tuberculosis. Over six weeks, the daily warfarin dose was increased from 3 to 10 mg to attain three consecutive in-clinic therapeutic INRs. She completed three complications-free months of warfarin treatment with time in therapeutic range (TTR) of 46%. We performed retrospective genetic testing to determine the patient's CYP2C9, CYP4F2, and VKORC1 genotypes and whether they had affected the interaction outcome. The analysis revealed that the subject carries CYP2C9*3*3 and VKORC1-1639 (GA) mutations, classifying her as a slow metabolizer and, hence, highly warfarin-sensitive. This was reflected on how the case responded to a relatively lower dose than previously reported cases that did not achieve the target on warfarin daily doses up to 35 mg. This is the first report addressing the genotype effect on this interaction. Patients with genetic variants requiring low warfarin doses are more likely to respond at a feasible dose while on rifampin. Future studies to evaluate warfarin-rifampin-gene interaction are warranted.
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Affiliation(s)
- Muhammad Salem
- Department of Pharmacy, Hamad General Hospital, Doha, Qatar
| | - Islam Eljilany
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | | | - Hazem Elewa
- College of Pharmacy, QU Health, Qatar University, Doha, Qatar.,Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
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9
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A case series of the rifampin-warfarin drug interaction: focus on practical warfarin management. Eur J Clin Pharmacol 2021; 77:341-348. [PMID: 33409685 DOI: 10.1007/s00228-020-03057-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 11/26/2020] [Indexed: 01/26/2023]
Abstract
PURPOSE To provide practical guidance by providing weekly descriptions of warfarin requirements for the onset and offset of the rifampin-warfarin interaction. METHODS A retrospective chart review within an outpatient Anticoagulation Clinic (AC). Patients were eligible for the onset phase provided they had known ambulatory-based warfarin steady-state requirements prior to rifampin initiation. For the offset phase, warfarin must be managed by the AC following rifampin discontinuation. Each phase was described separately with warfarin proportionate dose changes (median, IQR) for weeks 1, 2, and 4 as well as the change required to reach warfarin steady state. RESULTS Ten patients with 11 courses of warfarin-rifampin were included. For onset, clinicians should anticipate proportionate warfarin dose increases of 30-80% from week 1 to week 2 and a further 20-100% from week 2 to 4, with an overall warfarin dose increase of 165% (IQR 99, 227) to reach steady state at 30 days. For offset, clinicians should anticipate proportionate warfarin dose decreases of 15-25% for both week 1 and 2, and a further 20% for both week 3 and 4, resulting in an overall warfarin decrease of 67% (IQR - 70, - 58) to reach steady state at 4 weeks for most patients. CONCLUSION Close monitoring with at least twice weekly INRs for weeks 1 to 2 of both phases is needed to respond to substantially changing warfarin dose requirements. While inter- and intra-patient variability for proportionate warfarin dose changes for both the onset and offset of this drug interaction exists, our data provides general guidance.
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10
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Fahmi AM, Mohamed A, Elewa H, Saad MO. Preemptive Dose Adjustment Effect on the Quality of Anticoagulation Management in Warfarin Patients With Drug Interactions: A Retrospective Cohort Study. Clin Appl Thromb Hemost 2019; 25:1076029619872554. [PMID: 31482725 PMCID: PMC6829638 DOI: 10.1177/1076029619872554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
One strategy to manage patients on warfarin starting an interacting drug is to increase
the frequency of monitoring. Another strategy is to adjust warfarin dose around the time
patient is started on an interacting medication, which is known as “preemptive warfarin
dose adjustment.” The main objective of this study is to compare preemptive to
nonpreemptive strategy and their impact on the quality of anticoagulation management. This
is a retrospective cohort study performed at the pharmacist-managed anticoagulation clinic
in a tertiary hospital in the State of Qatar. Over a 4-year period, 340 patients were
evaluated, and 58 warfarin–drug interaction encounters were identified. Mean age of the
patients was (57.7 ± 13.7), and 50% of them were females. Preemptive dose adjustment was
used in 17 (29.3%) cases. Incidence of out-of-target international normalized ratio (INR)
was statistically lower in the preemptive arm compared to the control group (41.2% [7/17]
vs 69.2% [27/39], P = .048). Incidence of extreme out-of-target INR was
numerically lower in the preemptive arm compared to the control but did not reach
statistical significance (11.8% [2/17] vs 29.3% [12/41], P = .139).
Change in frequency of INR monitoring was not different between the 2 groups. However,
overall frequency of INR monitoring after onset/discontinuation of interacting medication
increased compared to baseline (7 [9] vs 21 [16] days, P < .001).
Preemptive strategy was shown in our study to decrease incidence of the out-of-target INR
visits, although patients remained in need for close monitoring.
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Affiliation(s)
| | - Adham Mohamed
- 1 Al Wakra Hospital, Hamad Medical Corporation, Al Wakra, Qatar
| | - Hazem Elewa
- 2 Clinical Pharmacy and Practice Section, College of Pharmacy, Qatar University, Doha, Qatar
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11
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Zhou L, Cui M, Zhao L, Wang D, Tang T, Wang W, Wang S, Huang H, Qiu X. Potential Metabolic Drug-Drug Interaction of Citrus aurantium L. ( Rutaceae) Evaluating by Its Effect on 3 CYP450. Front Pharmacol 2018; 9:895. [PMID: 30233359 PMCID: PMC6127460 DOI: 10.3389/fphar.2018.00895] [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] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 07/23/2018] [Indexed: 11/13/2022] Open
Abstract
Aim:Fructus aurantii (FA) is widely used in clinic as an expectorant and digestant herb in traditional Chinese medicine and proven to have a variety of pharmacological functions. FA is close to grapefruit either by botanical taxonomy or by their same components (flavonoids, etc.) and grapefruit has been proven to cause drug-drug interaction when co-administrated with CYP3A4 substrates. Besides, FA contains many compounds, such as flavonoids, which have been reported to impact the expressions of CYP450. However, the effect of FA on CYP450, whose change may affect drug safety and clinical efficacy attributed to drug-drug interaction, still remains unknown. Methods: The protein, mRNA expression and enzyme activity of CYP1A2, CYP3A4, and CYP2E1 in rat were determined by Western Blotting, RT-PCR method, the cocktail method, respectively, after orally administration of FA in succession for 7 days. CYP1A2, CYP3A4, and CYP2E1 mRNA expression were investigated in HepG2 cells following FA-medicated serum incubation for 24 h. Results: In rat, compared to the control group, CYP1A2, CYP3A4 protein, and mRNA expression were significantly induced consistent with the corresponding CYP activities; the protein expression of CYP2E1 was significantly upregulated, while the corresponding mRNA expression and enzyme activity showed no significant change. In HepG2 cells, compared to the control group, the mRNA expression of CYP1A2 and CYP3A4 was up-regulated statistically while CYP2E1 mRNA expression was not significantly induced or inhibited. Conclusion: FA may be a potential slight inducer of CYP1A2 and CYP3A4 and is unlikely to impact CYP2E1 until clinical researches are conducted.
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Affiliation(s)
- Lu Zhou
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Man Cui
- Medicine Service Section, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Shandong, China
| | - Linlin Zhao
- Health Management Center, Third Xiangya Hospital of Central South University, Changsha, China
| | - Dongsheng Wang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Tao Tang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Wenbo Wang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Sheng Wang
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
| | - Huiyong Huang
- Provincial Key Laboratory of Traditional Chinese Medicine Diagnostics, Hunan University of Chinese Medicine, Changsha, China
| | - Xinjian Qiu
- Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, China
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Moscovitz JE, Lin Z, Johnson N, Tu M, Goosen TC, Weng Y, Kalgutkar AS. Induction of human cytochrome P450 3A4 by the irreversible myeloperoxidase inactivator PF-06282999 is mediated by the pregnane X receptor. Xenobiotica 2017; 48:647-655. [PMID: 28685622 DOI: 10.1080/00498254.2017.1353163] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
1. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide (PF-06282999) is a member of the thiouracil class of irreversible inactivators of human myeloperoxidase enzyme and a candidate for the treatment of cardiovascular disease. PF-06282999 is an inducer of CYP3A4 mRNA and midazolam-1'-hydroxylase activity in human hepatocytes, which is consistent with PF-06282999-dose dependent decreases in mean maximal plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of midazolam in humans following 14-day treatment with PF-06282999. 2. In the present study, the biochemical mechanism(s) of CYP3A4 induction by PF-06282999 was studied. Incubations in reporter cells indicated that PF-06282999 selectively activated human pregnane X receptor (PXR). Treatment of human HepaRG cells with PF-06282999 led to ∼14-fold induction in CYP3A4 mRNA and 5-fold increase in midazolam-1'-hydroxylase activity, which was nullified in PXR-knock out HepaRG cells. TaqMan® gene expression analysis of human hepatocytes treated with PF-06282999 and the prototypical PXR agonist rifampin demonstrated increases in mRNA for CYP3A4 and related CYPs that are regulated by PXR. 3. Docking studies using a published human PXR crystal structure provided insights into the molecular basis for PXR activation by PF-06282999. Implementation of PXR transactivation assays in a follow-on discovery campaign should aid in the identification of back-up compounds devoid of PXR activation and CYP3A4 induction liability.
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Affiliation(s)
| | - Zhiwu Lin
- b Medicine Design, Pfizer Inc , Groton , CT , USA
| | | | - Meihua Tu
- a Medicine Design, Pfizer Inc , Cambridge , MA , USA and
| | | | - Yan Weng
- a Medicine Design, Pfizer Inc , Cambridge , MA , USA and
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Che JX, Shi JL, Lu Y, Liu YL. Validation of reference genes for normalization of gene expression by qRT-PCR in a resveratrol-producing entophytic fungus (Alternaria sp. MG1). AMB Express 2016; 6:106. [PMID: 27826948 PMCID: PMC5101243 DOI: 10.1186/s13568-016-0283-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 10/31/2016] [Indexed: 12/12/2022] Open
Abstract
Alternaria sp. MG1, an endophytic fungus isolated from Vitis vinifera, can independently produce resveratrol, indicating that this species contains the key genes for resveratrol biosynthesis. Identification of these key genes is essential to understand the resveratrol biosynthesis pathway in this strain, which is currently unknown in microorganisms. qRT-PCR is an efficient and widely used method to identify the key genes related to unknown pathways at the level of gene expression. Verification of stable reference genes in this strain is essential for qRT-PCR data normalization, although results have been reported for other Alternaria sp. strains. In this study, nine candidate reference genes including TUBA, EF1, EF2, UBC, UFD, RPS5, RPS24, ACTB and 18S were evaluated for expression stability in a diverse set of six samples representing different growth periods. We compared cell culture conditions and an optimized condition for resveratrol production. The comparison of the results was performed using four statistical softwares. A combination of TUBA and EF1 was found to be suitable for normalization of Alternaria sp. MG1 in different developmental stages, and 18S was found to be the least stable. The reference genes verified in this study will facilitate further research to explore gene expression and molecular mechanisms as well as the improvement of secondary metabolite yields in Alternaria sp. MG1. To our knowledge, this is the first validation of reference genes in Alternaria with the capability to produce resveratrol. Additionally, these results provide useful guidelines for the selection of reference genes in other Alternaria species.
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