Cytochrome allelic variants and clopidogrel metabolismin cardiovascular diseases therapy
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Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies used to treat the acute coronary syndrome (ACS) and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeutic efficiency of clopidogrel is controlled by the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrel into its active metabolites and, therefore, modify its turnover and clinical outcome. So far, clinical trials fail to confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.Cite
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Recent efforts directed at potential litigation in Hawai'i have resulted in a renewed interest for genetic screening for cytochrome P450 2C19 (CYP2C19) polymorphisms in patients treated with clopidogrel. Clopidogrel is an antiplatelet agent, frequently used in combination with aspirin, for the prevention of thrombotic complications with acute coronary syndrome and in patients undergoing percutaneous coronary interventions. Cytochrome P-450 (CYP) 2C19 is an enzyme involved in the bioactivation of clopidogrel from a pro-drug to an active inhibitor of platelet action. Patients of Asian and Pacific Island background have been reported to have an increase in CYP2C19 polymorphisms associated with loss-of-function of this enzyme when compared to other ethnicities. This has created an interest in genetic testing for CYP2C19 polymorphisms in Hawai'i. Based upon our review of the current literature, we do not feel that there is support for the routine screening for CYP2C19 polymorphisms in patients being treated with clopidogrel; furthermore, the results of genetic testing may not be helpful in guiding therapeutic decisions. We recommend that decisions on the type of antiplatelet treatment be made based upon clinical evidence of potential differential outcomes associated with the use of these agents rather than on the basis of genetic testing.
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Ticlopidine
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Clopidogrel is a pro-drug which is converted to an active metabolite that selectively blocks ADP-dependent platelet activation and aggregation. The main enzyme responsible for activating clopidogrel is the cytochrome P450 (CYP) isoenzyme CYP2C19, which is polymorphic. There is a growing body of literature showing that carriers of variant CYP2C19 alleles have impaired ability to metabolize clopidogrel (i.e. poor metabolizers), which is associated with decreased inhibition of platelet aggregation and increased cardiovascular risk. Some proton pump inhibitors are also metabolized by the CYP2C19 enzyme and often given together with clopidogrel to reduce gastrointestinal side effects. In particular, omeprazole has been shown to inhibit the CYP-mediated metabolism of clopidogrel, and some studies have shown that the combination was associated with a higher incidence of cardiovascular adverse reactions than clopidogrel given alone. However, a recent randomized controlled trial demonstrated no significant difference in adverse cardiovascular events for patients on the combination of clopidogrel and omeprazole compared with clopidogrel alone. This current review aims to summarize the role of pharmacogenetics and drug interactions in determining variability in response to clopidogrel.
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Clopidogrel therapy in combination with proton pump inhibitors (PPIs) is controversial in the treatment for ischemic heart diseases after coronary stent implantation because PPIs (especially omeprazole) are suggested to attenuate the antiplatelet effect of clopidogrel. The polymorphic CYP2C19 enzyme has a pivotal function in the metabolism of both agents. In addition, omeprazole can irreversibly inhibit the activity of CYP2C19 enzyme. The frequency of CYP2C19 polymorphisms with a poor metabolizer phenotype is especially high (29-35%) in the Asian population. The present study investigated whether CYP2C19 genotyping is required in clopidogrel-treated patients with concomitant omeprazole treatment for genetically at risk poor metabolizing CYP2C19 populations. In this study literature was searched and reviewed which comprised the specific research area. The results indicated that omeprazole in combination with clopidogrel is related to a higher recurrence risk of adverse cardiovascular events and a higher mortality rate. Interestingly, the antiplatelet effect of clopidogrel was more affected by omeprazole in homozygous CYP2C19*1 carries than in heterozygous (*1/2 or *1/3) and homozygous (*2/2 or *2/3) CYP2C19 carriers. Therefore, CYP2C19 genotyping is advised in clopidogrel-treated patients with concomitant omeprazole treatment. This to prevent adverse cardiovascular events in clopidogrel treated patients in combination with PPIs. However, the number of studies is rather limited up till now in relation to the CYP2C19 status and the combination of omeprazole plus clopidogrel. Therefore further clinical studies are indispensable to verify the conclusion in this study.
Lansoprazole
Concomitant
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Active metabolism of clopidogrel is mainly mediated by CYP2C19. There are genetic differences in the activity of CYP2C19. Therefore, active metabolism of clopidogrel is affected by CYP2C19 genotypes. The main metabolizing enzyme of proton pump inhibitors (PPIs) is CYP2C19. Therefore, the anti-platelet function of clopidogrel is attenuated by concomitant use of PPIs. There are differences in the metabolic disposition among different PPIs. Affinity to CYP2C19 differs among different PPIs.Whether a PPI attenuates the efficacy of clopidogrel depends on CYP2C19. Individuals who are decreased metabolizers, i.e. carriers the allele of CYP2C19*2 and/or *3, are more likely to convert from 'responder' to 'non-responder' to clopidogrel when placed on a concomitant PPI. We found that rabeprazole, whose affinity to CYP2C19 has been considered lower, attenuated the efficacy of clopidogrel. * We tested whether the separate dosing of a PPI and clopidogrel decreased the risk of attenuation of clopidogrel efficacy. We unfortunately found that separate dosing did not avoid the problematic interaction between clopidogrel and a PPI in subject's with CYP2C19*2 and/or CYP2C19*3.The efficacy of clopidogrel is influenced by CYP2C19 genotypes and substrates of CYP2C19, such as proton pump inhibitors (PPIs). We assessed the influence of three different PPIs on the anti-platelet function of clopidogrel in relation to CYP2C19 genotype status.Thirty-nine healthy volunteers with different CYP2C19 genotypes took clopidogrel 75 mg with or without omeprazole 20 mg, lansoprazole 30 mg or rabeprazole 20 mg in the morning for 7 days. The influence of the three PPIs on the anti-platelet function of clopidogrel was determined. A less than 30% inhibition of platelet aggregation (IPA) during clopidogrel dosing was defined as a 'low responder'. We also examined whether evening dosing of omeprazole could prevent the interaction with clopidogrel dosed in the morning.In rapid metabolizers (RMs, *1/*1, n=15) of CYP2C19, omeprazole and rabeprazole significantly attenuated the anti-platelet function of clopidogrel. In decreased metabolizers (DMs, carriers of *2 and/or *3, n=24), there was a large variation in IPA and there was a trend but no significant decrease in IPA when placed on a concomitant PPI. Some DMs became 'low-responders' when placed on a concomitant PPI. Evening omeprazole dose in RMs did not seem to cause a significant decrease in IPA in contrast to morning dosing, but did so in DMs.The three PPIs affected the efficacy of clopidogrel to different degrees. Both omeprazole and rabeprazole significantly decreased IPA in RMs but not DMs, although there was a trend towards lower IPA in DMs. Morning and evening dosing of omeprazole were both associated with lower IPA in DMs.
Rabeprazole
Lansoprazole
Esomeprazole
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Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies used to treat the acute coronary syndrome (ACS) and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeutic efficiency of clopidogrel is controlled by the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrel into its active metabolites and, therefore, modify its turnover and clinical outcome. So far, clinical trials fail to confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.
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Background: Clopidogrel is one of the most frequently prescribed antiplatelet agents to reduce the risk of atherosclerotic symptoms. CYP2C19 enzyme is involved in clopidogrel metabolism, and several genetic variations of CYP2C19gene are able to affect the clinical response of clopidogrel. Despite the lack of a fully accepted guideline for CYP2C19 pharmacogenetic testing before clopidogrel treatment by relevant communities, we believe that determination of the variant frequencies is important to predict the efficiency and possible clopidogrel related risks before the initiation of treatment on the basis of populations. Our aim was to determine the distribution of gene polymorphisms affecting the enzyme activity in Turkish cardiac patients prescribed clopidogrel. Methods: 54 clopidogrel prescribed patients were included in the study. The presence of CYP2C19*2, *3, *4, *5, *6, *7, *8, *9, *10 and *17 polymorphisms were investigated using a microarray platform. Results : No variant allele was detected for *4, *5, *6, *7, *8, *9 and *10 polymorphisms. The genotype frequencies were detected as 38.89% for *1/*1, 16.67% for *1/*2, 11.11% for *2/*17, 1.85% for *1/*3, 1.85% for *2/*3, 27.78% for *1/*17 and 1.85% for *17/*17. According to genotype analysis, 1.85% of the patients were recorded as poor and 29.63% intermediate; whereas 27.78% as rapid and 1.85% ultra-rapid metabolizers. Conclusion: Although our study population does not consist of a high number of patients, since the high frequency of intermediate, rapid and ultra-rapid metabolizer patients were detected in relatively high frequencies, CYP2C19 polymorphisms should be taken into account for efficiency and possible clopidogrel related risks in Turkish cardiac patients.
Turkish population
Guideline
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Clopidogrel and aspirin are among the most prescribed dual antiplatelet therapies to treat the acute coronary syndrome and heart attacks. However, their potential clinical impacts are a subject of intense debates. The therapeuticefficiencyof clopidogrel iscontrolledby the actions of hepatic cytochrome P450 (CYPs) enzymes and impacted by individual genetic variations. Inter-individual polymorphisms in CYPs enzymes affect the metabolism of clopidogrelintoitsactivemetabolitesand,therefore,modify its turnover and clinical outcome.Sofar, clinical trials failto confirm higher or lower adverse cardiovascular effects in patients treated with combinations of clopidogrel and proton pump inhibitors, compared with clopidogrel alone. Such inconclusive findings may be due to genetic variations in the cytochromes CYP2C19 and CYP3A4/5. To investigate potential interactions/effects of these cytochromes and their allele variants on the treatment of acute coronary syndrome with clopidogrel alone or in combination with proton pump inhibitors, we analyze recent literature and discuss the potential impact of the cytochrome allelic variants on cardiovascular events and stent thrombosis treated with clopidogrel. The diversity of CYP2C19 polymorphisms and prevalence span within various ethnic groups, subpopulations and demographic areas are also debated.
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