An insight into the interaction between clopidogrel and proton pump inhibitors

Platelet activation and aggregation have been established as pivotal elements in the pathogenesis of atherosclerotic and ischemic diseases, including acute coronary syndromes. The difficulty of achieving optimal platelet inhibition remains a major constraint following dual-antiplatelet therapy, which can lead to a diminished response following initiation of clopidogrel therapy. Though the absolute mechanisms underlying clopidogrel resistance are controversial, a variety of responsible factors are recognized. Clopidogrel, being a prodrug, requires conversion to an active metabolite for its activity. This metabolism involves various cytochrome P450 (CYP) enzymes at different steps, and it is hypothesized that competitive inhibition of CYPs may contribute to clopidogrel resistance. Proton pump inhibitors (PPIs) are competitive inhibitors of CYPs that can attenuate the antiplatelet activity of clopidogrel, and this can lead to clopidogrel resistance. Available data from different clinical studies have postulated the possibility of a drug-drug interaction between clopidogrel and PPIs. PPIs differ somewhat in their pharmacokinetic properties like bioavaibility and affinity for CYP2C19. However it is not clear whether the proposed drug interaction of PPI with clopidogrel is same with all PPIs (i.e., a class effect) or it is limited to a subset of PPIs (i.e., a drug effect). This interaction needs further assessment with well designed prospective clinical trials, before any change in clinical practice should be considered. In this review, we attempt to evaluate the available evidence exploring drug interactions with PPIs as the underlying mechanism for the reduced antiplatelet effect of clopidogrel.     

Identification of the Significant Involvement and Mechanistic Role of CYP3A4/5 in Clopidogrel Bioactivation

相似文献   

Interactions between clopidogrel and proton pump inhibitors: a review of evidence

Clopidogrel is a thienopyridine, which inhibits the platelet P2Y adenosine diphosphate (ADP) receptor termed P2Y(12). It is taken as a prodrug that requires biotransformation to an active metabolite by cytochrome P450 (CYP) isoenzymes. In addition, esterases shunt the majority of clopidogrel to an inactive pathway, whilst the remaining prodrug requires two separate CYP-dependent oxidative steps. PPIs might diminish the antiplatelet effects and the clinical effectiveness of clopidogrel possibly through inhibition of CYP2C19 and CYP3A4 isoenzymes. Treatment with clopidogrel and aspirin decreases recurrent cardiovascular events after an acute coronary syndrome. However, an inherent increment of major bleeding is also associated with antiplatelet therapy, as well as dyspepsia with aspirin. Also, major bleeding has been associated with high risk for ischemic events and mortality. For this reason, a proton pump inhibitor (PPI) is often co-prescribed to reduce the risk of gastrointestinal tract bleeding, but its concomitant use might reduce the inhibitory effect of clopidogrel on platelet aggregation. Nevertheless, doubts exist about the possible interaction of concomitant PPI use that may reduce the inhibitory effect of clopidogrel on platelet aggregation. Indeed, there is some controversy with regard to the true risk of cardiovascular adverse events arising from a potential drug-drug interaction between clopidogrel and PPI. In this article, we will review the current status and controversies in relation to a possible interaction between clopidogrel and PPIs.     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel's inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H(2)-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.     

Different effects of proton pump inhibitors and famotidine on the clopidogrel metabolic activation by recombinant CYP2B6, CYP2C19 and CYP3A4

Inhibitory potential of proton pump inhibitors (PPIs) and famotidine, an H(2) receptor antagonist, on the metabolic activation of clopidogrel was evaluated using recombinant CYP2B6, CYP2C19 and CYP3A4. Formation of the active metabolite from an intermediate metabolite, 2-oxo-clopidogrel, was investigated by liquid chromatography-tandem mass spectrometry and three peaks corresponding to the pharmacologically active metabolite and its stereoisomers were detected. Omeprazole potently inhibited clopidogrel activation by CYP2C19 with an IC(50) of 12.8 μmol/L and more weakly inhibited that by CYP2B6 and CYP3A4. IC(50) of omeprazole for CYP2C19 and CYP3A4 was decreased about two- and three-fold, respectively, by 30-min preincubation with NADPH. Lansoprazole, esomeprazole, pantoprazole, rabeprazole and rabeprazole thioether, a major metabolite, also inhibited metabolic activation by CYP2C19, with an IC(50) of 4.3, 8.9, 48.3, 36.2 and 30.5 μmol/L, respectively. In contrast, famotidine showed no more than 20% inhibition of clopidogrel activation by CYP2B6, CYP2C19 and CYP3A4 at up to 100 μmol/L and had no time-dependent CYP2C19 and CYP3A4 inhibition. These results provide direct evidence that PPIs inhibit clopidogrel metabolic activation and suggest that CYP2C19 inhibition is the main cause of drug-drug interaction between clopidogrel and omeprazole. Famotidine is considered as a safe anti-acid agent for patients taking clopidogrel.     

Interaction between clopidogrel and proton-pump inhibitors

The American Heart Association/American College of Cardiology guidelines recommend initiating a proton-pump inhibitor (PPI) to prevent gastrointestinal bleeding if patients are receiving concomitant therapy with clopidogrel and aspirin. Recently, concern has been raised regarding the ability of PPIs to decrease the antiplatelet activity of clopidogrel. To date, there are 16 studies that evaluated the outcomes of using clopidogrel with a PPI. One of the studies has shown that adding lansoprazole to clopidogrel has no effect on the concentration of clopidogrel’s inactive metabolite. The eight clinical trials that studied the effect of using PPIs and clopidogrel together on platelet function testing have shown differing effects between PPIs. Concurrent omeprazole and clopidogrel use was shown to decrease the antiplatelet effects of clopidogrel in three studies; whereas pantoprazole, lansoprazole and esomeprazole have been shown to have no significant effect on the antiplatelet response to clopidogrel. Six other studies showed that using PPIs and clopidogrel together led to adverse clinical outcomes; however, one study that did a separate analysis on pantoprazole, showed that using pantoprazole with clopidogrel had no significant impact on clinical outcomes. Post hoc analysis from a large randomized trial comparing prasugrel with clopidogrel indicated no clinically significant effects of PPIs in patients treated with either prasugrel or clopidogrel. Preliminary results from a prospective, randomized trial comparing cardiovascular clinical outcomes between omeprazole and placebo in clopidogrel-treated patients have been reported and suggest no interaction. However, the study was stopped prematurely secondary to loss of funding and follow-up limited to a median of 133 days so no firm conclusions were drawn. The data currently available regarding concurrent clopidogrel and PPI use are limited, so further studies are needed to provide a definite conclusion. Until additional prospective studies are available, the use of clopidogrel with a PPI should be avoided, if possible, and a H₂-receptor antagonist be selected instead. Prasugrel may be administered safely with a PPI as there is currently no evidence of a pharmacokinetic, pharmacodynamic or adverse clinical effects.     

质子泵抑制剂与氯吡格雷药物相互作用研究进展

对2010年Mdeline收载的关于质子泵抑制剂(PPIs)与氯吡格雷相互作用的研究文献进行综述分析,PPIs对氯吡格雷抗血小板聚集活性的影响与多个因素相关:氯吡格雷和阿司匹林合用时,PPIs与氯吡格雷之间无临床意义的药物相互作用;当单用氯吡格雷抗血小板聚集时,PPIs对其药效的影响显著,而且不同的PPIs之间的作用强度有差异;以微观指标(如ADP或花生四烯酸诱导的血小板聚集度)为标准,则氯吡格雷和PPIs之间存在不良药物相互作用,但以宏观指标(如一级事件发生率)为标准则无临床意义的不良药物相互作用;PPIs对氯吡格雷的影响与CYP2C19基因多态性有关:快代谢型患者PPIs对氯吡格雷的抗血小板聚集作用影响显著,慢代谢型无明显影响;与单用氯吡格雷相比,PPI+阿司匹林可以显著降低胃肠道出血事件,对心血管系统没有不良影响。因此,对于PCI术后短期内行氯吡格雷和阿司匹林双抗血小板聚集患者,临床可以根据情况选择任何一个PPIs;对于单用氯吡格雷抗血小板聚集的患者,应该首选与泮托拉唑合用;PPIs合用阿司匹林能有效抗血小板聚集,而且显著减少胃肠道出血事件,因此在必须应用PPIs的情况下,阿司匹林是氯吡格雷的一个有效替代药物。     

Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes

AIMS

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.     

Genetic polymorphisms of CYP2C19 influences the response to clopidogrel in ischemic heart disease patients in the South Indian Tamilian population

Background

The antiplatelet activity of clopidogrel is variable among patients suffering from ischemic heart disease. Variation in the cytochrome P450 2C19 (CYP2C19) gene coding for the CYP2C19 enzyme is one of the major determinants of this variable response to clopidogrel. The activity of the CYP2C19 enzyme, which plays a role in the conversion of the prodrug clopidogrel to its active metabolite, is genetically influenced by polymorphisms in its gene. The aim of our study was to evaluate the association of CYP2C19 polymorphisms and the antiplatelet effect of clopidogrel in the South Indian Tamilian population.

Materials and methods

Genotyping and platelet aggregation results of 149 ischemic heart disease patients on clopidogrel maintenance therapy (75 mg daily dose) were analyzed in this study. CYP2C19 polymorphisms were genotyped by the PCR-restriction fragment length polymorphism method. We measured residual platelet activities in these patients on clopidogrel therapy in terms of impedance (expressed as ohms). The study subjects were divided into two metabolizer phenotype groups [group 1: poor/intermediate metabolizers (PM/IM); group 2: extensive/ultra-rapid metabolizers (EM/URM)] based on CYP2C19 genotype, and the residual platelet activities were compared. Higher values of impedance denote increased residual platelet activity.

Results

Poor/intermediate metabolizers had significantly higher impedance values than EM/URM [(median; range) 4.0; 0–13 vs. 2.0; 0–11, respectively; p?=?0.04]. These higher impedance values denote higher residual platelet activities among the carriers of loss-of-function alleles (CYP2C19*2,*3) than among non-carriers. However, residual platelet activities were lower among the carriers of the gain-of-function allele (CYP2C19*17) than among non-carriers, although this difference was not significant.

Conclusion

Patients with CYP2C19 (*2 or *3) genetic polymorphisms had higher residual platelet activities and were associated with a reduced antiplatelet response to clopidogrel. As the South Indian Tamilian population is characterized with higher frequencies of these genetic polymorphisms, our findings mandate further studies aimed at initiating genome-based personalized antiplatelet therapy.     

Inconsistencies surrounding the risk of adverse outcomes with concomitant use of clopidogrel and proton pump inhibitors

INTRODUCTION: There is considerable debate surrounding the clinical relevance of an adverse interaction between clopidogrel and proton pump inhibitors (PPIs). Some studies have indicated that PPIs may attenuate the antiplatelet efficacy of clopidogrel, thus leading to increased risk of thrombotic cardiovascular events. AREAS COVERED: From a literature search of MEDLINE and EMBASE, the authors critically appraised data from systematic reviews, randomised controlled trials and observational studies that evaluated platelet function and clinical outcomes in patients receiving concomitant clopidogrel and PPIs. EXPERT OPINION: The evidence from platelet function and cardiovascular outcome studies is highly inconsistent. Higher quality data from randomised trials indicate that use of PPI therapy for up to 6 months is unlikely to cause any adverse interaction with clopidogrel, and there are gastrointestinal benefits with PPI use.     

Effects of drug interactions on biotransformation and antiplatelet effect of clopidogrel in vitro

BACKGROUND AND PURPOSE

The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.

EXPERIMENTAL APPROACH

Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.

KEY RESULTS

Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 µM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 µM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC₅₀ values of 0.03 ± 0.07 µM and 0.55 ± 0.06 µM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 µM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations ≤10 µM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.

CONCLUSIONS AND IMPLICATIONS

At clopidogrel concentrations >10 µM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations ≤10 µM. CYP2C19 inhibition by clopidogrel at concentrations >10 µM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.     

Pharmacogenomics of proton pump inhibitors

Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are metabolized by cytochrome P450 isoenzyme 2C19 (CYP2C19) in the liver. There are genetic differences that affect the activity of this enzyme. The genotypes of CYP2C19 are classified into three groups: homozygous extensive metabolizer (homEM), heterozygous extensive metabolizer (hetEM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs differ among the different CYP2C19 genotype groups. Plasma PPI and intragastric pH levels during PPI treatment are the lowest in the homEM group and the highest in the PM group. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs are reflected in the cure rates for gastroesophageal reflux disease and Helicobacter pylori infection with PPI-based therapies. The CYP2C19 genotyping test is a useful tool for deciding on the optimal treatment regimen using a PPI, including a dual (PPI plus antibiotic) or a triple (PPI plus two antibiotics) therapy.     

Effects of omeprazole and genetic polymorphism of CYP2C19 on the clopidogrel active metabolite

Clopidogrel is an antiplatelet agent widely used in cardiovascular diseases and an inactive prodrug that needs to be converted to an active metabolite in two sequential metabolic steps. Several CYP450 isoforms involved in these two steps have been described, although the relative contribution in vivo of each enzyme is still under debate. CYP2C19 is considered to be the major contributor to active metabolite formation. In the current study, net CYP2C19 contribution to the active metabolite formation was determined from exposure of the active metabolite in two clinical studies (one phase I study with well balanced genetic polymorphic populations and a meta-analysis with a total of 396 healthy volunteers) at different clopidogrel doses. CYP2C19 involvements were estimated to be from 58 to 67% in intermediate metabolizers (IMs), from 58 to 72% in extensive metabolizers (EMs), and from 56 to 74% in ultrarapid metabolizers (UMs), depending on the study and the dose. For this purpose, a static model was proposed to estimate the net contribution of a given enzyme to the secondary metabolite formation. This static model was compared with a dynamic approach (Simcyp model) and showed good consistency. In parallel, in vitro investigations showed that omeprazole is a mechanism-based inhibitor of CYP2C19 with K(I) of 8.56 μM and K(inact) of 0.156 min(-1). These values were combined with the net CYP2C19 contribution to the active metabolite formation, through a static approach, to predict the inhibitory effect at 80-mg omeprazole doses in EM, IM, and UM CYP2C19 populations, with good consistency, compared with observed clinical values.     

Efficacy and safety of concomitant use of rabeprazole during dual-antiplatelet therapy with clopidogrel and aspirin after drug-eluting stent implantation: a retrospective cohort study

After coronary stent implantation, dual-antiplatelet therapy (DAT), such as aspirin and clopidogrel, is essential to prevent stent thrombosis. Proton-pump inhibitors (PPIs) may be used to prevent gastrointestinal (GI) bleeding during DAT, but there is no evidence for the efficacy of PPIs in this setting. Because both clopidogrel and PPIs are metabolized by cytochrome P450 (CYP) 2C19, there is a possibility that, through drug interaction, PPIs diminish the antiplatelet effect of clopidogrel. In this retrospective cohort study, we evaluated the efficacy and safety of rabeprazole in patients receiving DAT of clopidogrel and aspirin after drug-eluting stent implantation. In 199 patients treated with DAT alone (control group) and 103 patients treated with rabeprazole plus DAT (rabeprazole group), we examined the incidences of GI bleeding and major adverse cardiac events (MACE) including stent thrombosis. The incidence of GI bleeding was not significantly different between the groups (hazard ratio 0.47 [95% confidence interval 0.15-1.42], P=0.18; P=0.17 in log-rank test), although no patient with severe bleeding was observed in the rabeprazole group. The use of rabeprazole did not increase the incidence of MACE (hazard ratio 1.28 [95% confidence interval 0.54-3.00], P=0.56; P=0.56 in log-rank test). One patient who developed subacute stent thrombosis under DAT was genetically proven to be a CYP2C19 poor metabolizer. The effect of rabeprazole to prevent GI bleeding is limited in patients receiving DAT. It remains to be confirmed whether these results may depend on CYP2C19 polymorphisms or a class of PPIs.     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

Drug–drug interaction of rabeprazole and clopidogrel in healthy Chinese volunteers

Purpose

This study was aimed to determine the impact of rabeprazole (RBRZ) on the antiplatelet efficacy of clopidogrel (CPG) in healthy Chinese volunteers, and further to predict the effect of CYP2C19 genetic polymorphism on the efficacy of rabeprazole and clopidogrel.

Methods

The open-label, two period cross-over study was conducted in 20 healthy Chinese subjects with different CYP2C19 genotypes receiving clopidogrel, rabeprazole or the two drugs, respectively. All the volunteers were divided into two groups, poor metabolizers (PMs) and extensive metabolizers (EMs), depending on CYP2C19 genotypes. Blood samples were collected at baseline and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 h after administration. The plasma concentrations of rabeprazole and clopidogrel were analyzed by LC-MS/MS and ADP-induced platelet aggregation was detected by the optical turbidimetric method.

Results

There were no significant differences in the mean plasma concentration–time curves of clopidogrel (CPG), the inactive metabolite clopidogrel carboxylic acid (CPG-CA), the active metabolite clopidogrel-MP-Derivative (MP-AM), and rabeprazole (RBRZ) according to the co-administration of CPG and RBRZ. There were no major changes in the pharmacokinetics of CPG and RBRZ. The maximal ADP-induced platelet aggregation (2 μmol/L) was decreased in EMs compared with PMs.

Conclusion

Co-administration of rabeprazol and clopidogrel did not affect the antiplatelet efficacy of clopidogrel. The CYP2C19 genetic polymorphism may impact the efficacy of clopidogrel.     

Variability in response to clopidogrel: how important are pharmacogenetics and drug interactions?

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.     

Pharmacogenetics of P2Y12 receptor inhibitors

Oral P2Y₁₂ inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events after an acute coronary syndrome and percutaneous coronary intervention (PCI) in the absence of genotyping. However, both are associated with an increased risk for non-coronary artery bypass-related bleeding. Clopidogrel is a prodrug requiring bioactivation, primarily via the CYP2C19 enzyme. Approximately 30% of individuals have a CYP2C19 no function allele and decreased or no CYP2C19 enzyme activity. Clopidogrel-treated carriers of a CYP2C19 no function allele have decreased exposure to the clopidogrel active metabolite and lesser inhibition of platelet aggregation, which likely contributed to reduced clopidogrel efficacy in clinical trials. The pharmacogenetic data for clopidogrel are most robust in the setting of PCI, but evidence is accumulating for other indications. Guidance is available from expert consensus groups and regulatory agencies to assist with integrating genetic information into P2Y₁₂ inhibitor prescribing decisions, and CYP2C19 genotype-guided antiplatelet therapy after PCI is one of the most common examples of clinical pharmacogenetic implementation. Herein, we review the evidence for pharmacogenetic associations with clopidogrel response and outcomes with genotype-guided P2Y₁₂ inhibitor selection and describe guidance to assist with pharmacogenetic implementation. We also describe processes for applying genotype data for P2Y₁₂ inhibitor therapy selection and remaining gaps in the field. Ultimately, consideration of both clinical and genetic factors may guide selection of P2Y₁₂ inhibitor therapy that optimally balances the atherothrombotic and bleeding risks.     

Pharmacogenetics of the proton pump inhibitors: a systematic review

Cytochrome P450 (CYP) 2C19 mediates the major metabolic transformations of the proton pump inhibitors (PPIs) omeprazole, pantoprazole, lansoprazole, esomeprazole, and rabeprazole. Genetic polymorphism of CYP2C19 can lead to significant phenotypic variation in the activity of this isoenzyme and thus in the metabolism of PPIs. We systematically reviewed the pharmacogenetic studies of PPIs with respect to the effects of CYP2C19 polymorphism on the clinical outcomes of PPI therapy. We searched MEDLINE (January 1966-August 2002) and EMBASE (January 1988-August 2002) for English-language articles on the pharmacogenetics of PPIs; the search was supplemented by a bibliographic review of all relevant articles. Seventeen pertinent citations were identified, and the quality (level) of evidence for each was categorized according to the rating scale of the United States Preventive Services Task Force. We found that the relationship between CYP2C19 genetic polymorphism and clinical outcomes after PPI therapy has not yet been clearly delineated. Virtually all pharmacogenetic studies of PPIs have been performed in Japanese men; thus, the clinical relevance of CYP2C19 genetic polymorphism in non-Asian patients and women is unknown. Differences among dual- and triple-therapy drug regimens make it difficult to compare H. pylori eradication studies and assess their applicability to current practice patterns. Drug adherence, a pivotal factor in the success of eradication therapy, was addressed in only four trials. Future directions for research include performing more studies with larger sample sizes, particularly in non-Asian populations and women; measuring plasma PPI concentrations to directly correlate H. pylori infection and ulcer cure rates with plasma drug availability; expanding the study population to patients with gastroesophageal reflux disease; and exploring the influence of CYP3A4 in the success or failure of PPI therapy. Although CYP2C19 genotyping is currently only a research instrument, it may be a valuable clinical tool in select patients to ensure optimal PPI therapy.     

Differential inhibitory effects of proton pump inhibitors on the metabolism and antiplatelet activities of clopidogrel and prasugrel

The interaction between proton pump inhibitors (PPIs) and clopidogrel/prasugrel was investigated. The IC50 values of omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole on the metabolic ratios of 2-oxo-clopidogrel/clopidogrel, H4 (the active metabolite of clopidogrel)/2-oxo-clopidogrel and R-138727 (the active metabolite of prasugrel)/prasugrel thiolactone in human liver microsomes were determined. The antiplatelet activities of clopidogrel and prasugrel were measured with or without PPIs. As a result, most PPIs (except for pantoprazole) inhibited the formation of 2-oxo-clopidogrel with IC50 values of 20-32 μm and inhibited the formation of H4 with IC50 values of 6-20 μm. PPIs inhibited the formation of R-138727 with IC50 values of 9-25 μm. Among the tested PPIs, omeprazole exhibited the highest inhibitory potency on the formation of H4. Omeprazole, esomeprazole and rabeprazole exhibited the highest inhibitory potencies on the formation of R-138727. For platelet aggregation, omeprazole and lansoprazole show higher inhibitory effects on the antiplatelet activity of clopidogrel. On the other hand, omeprazole, esomeprazole and rabeprazole significantly decreased the antiplatelet activity of prasugrel thiolactone. These data indicate that PPIs differ in their effects of inhibiting the metabolism and antiplatelet activities of clopidogrel and prasugrel.