Clopidogrel, CYP2C19 and proton pump inhibitors: What we know and what it means

Hariharan, S.; Southworth, Mary Ross; Madabushi, Rajanikanth

doi:10.1002/jcph.337

Cited by 9 publications

(7 citation statements)

References 39 publications

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“…Clopidogrel, a prodrug, is an irreversible inhibitor of P2Y12 receptor and requires metabolic activation by CYP450. The attenuated antiplatelet effect was reported to be more prominent with omeprazole or esomeprazole than with other PPIs such as dexlansoprazole or lansoprazole [36]. Pantoprazole or H 2 blockers may be considered as alternative gastroprotective agents.…”

Section: Discussionmentioning

confidence: 99%

Prevalence and Risk Factors of Potential Drug Interactions in Hospitalized Cardiovascular Patients Using Three Knowledge Bases

Raslan¹,

Hassan²,

El-Mahdy³

et al. 2018

JAMPS

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Background: Drug interactions continue to be an important cause of adverse effects, especially with cardiovascular drugs. Objective: This cross-sectional observational study aimed to recognize the frequency of potential drug-drug interactions (pDDIs) using three electronic knowledge bases (KBs); Lexicomp ® , Micromedex ® , and the free Drugs.com®, compare the inclusion and gradings of pDDIs in these three KBs and to identify associated risk factors. Methods: Medication orders of 125 patients in the cardiovascular department and its intensive care unit (ICU) of Assiut University Hospitals, Egypt were screened for pDDIs. Results: About 88.8% of the patients were prescribed five or more drugs. A sum of 1206 pDDIs was found which comprised of 245 different interacting pairs. Overall, 96.8% of the patients had at least

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Section: Discussionmentioning

confidence: 99%

Prevalence and Risk Factors of Potential Drug Interactions in Hospitalized Cardiovascular Patients Using Three Knowledge Bases

Raslan¹,

Hassan²,

El-Mahdy³

et al. 2018

JAMPS

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“…The role of CYP2C19 has been extensively investigated and factors affecting clopidogrel's antiplatelet activity include but are not limited to loss-of-function alleles and potent CYP2C19 inhibition [4,5,8]. Polymorphic expression of CYP2C9 and CYP3A4 has also been shown to affect the bioactivation of clopidogrel [6,7], so does the inhibition or induction of CYP3A4 [8].…”

Section: Discussionmentioning

confidence: 99%

“…Clinical studies have shown that the loss-of-function alleles of CYP2C19 as well as CYP2C19 inhibitors lead to lower exposure to the active metabolite and reduced antiplatelet activity [4,5]. Contributions of CYP2C9 and CYP3A4 to clopidogrel bioactivation have also been described [6,7,8].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation

Shao

Lu²,

Xu³

et al. 2015

Pharmacology

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Background: Patients with diabetes have increased rates of cardiovascular events, and concomitant use of antidiabetic agents and clopidogrel may increase the risk for drug interactions. This study was undertaken to investigate the interaction potential between sulfonylurea drugs and clopidogrel, with an emphasis on key steps in the clopidogrel bioactivation processes. Methods: Inhibition of clopidogrel metabolism by sulfonylureas was evaluated by monitoring the formation of clopidogrel carboxylic acid and 2-oxo-clopidogrel in human liver microsomes (HLM), human intestinal microsomes and recombinant human enzymes. CYP2C9-based interaction was investigated for both 2-oxo-clopidogrel and glimepiride using HLM and the recombinant CYP2C9 system. Results: For the formation of clopidogrel carboxylic acid (the deactivation step) and 2-oxo-clopidogrel (the first step of bioactivation) in human microsomes, the inhibition potency of the 3 sulfonylurea drugs tested followed the order of glimepiride > glipizide > gliclazide. For the metabolism of 2-oxo-clopidogrel (the second step of bioactivation), glimepiride demonstrated a relatively strong inhibition against CYP2C9 activity (IC₅₀ 12.7 μmol/l). In addition, 2-oxo-clopidogrel displayed a moderate inhibitory effect toward the CYP2C9-mediated metabolism of glimepiride. Conclusion: The moderate inhibition observed for clopidogrel bioactivation may not present a significant risk for drug-drug interactions between sulfonylureas and clopidogrel. While these findings bode well for multidrug therapies involving sulfonylureas and clopidogrel, clinical investigations are needed to define the clinical risk and benefit for combining these agents for the management of cardiovascular events in diabetic patients.

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“…[ 3 ] Clopidogrel monotherapy or in combination with aspirin is widely used in the antiplatelet therapy of CCVD patients to reduce the occurrence of ischemic cardiovascular events, but it could also lead to an increased bleeding risk. [ 4 5 ] Common CYP2C19 polymorphisms are detected to influence pharmacodynamic response to clopidogrel, and loss-of-function CYP2C19 polymorphisms could result in reduced exposure to the active metabolite of clopidogrel. [ 6 ] This could decrease patient responsiveness to clopidogrel, and a low responsiveness is tied up with increased risk of ischemic events.…”

Section: Introductionmentioning

confidence: 99%

Effect of cytochrome P450 2C19*17 allelic variant on cardiovascular and cerebrovascular outcomes in clopidogrel-treated patients: A systematic review and meta-analysis

et al. 2017

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Background:We aimed to evaluate the associations of gain-of-function allele of CYP2C19*17 and risk of clinical events in clopidogrel-treated patients with cardiovascular and cerebrovascular diseases (CCVDs).Materials and Methods:Literature search was conducted in PubMed, EMBASE, and Cochrane Library. Odds ratio (OR) combined with 95% confidence interval (CI) was the pooled statistics. Subgroup analysis was performed by disease type, bleeding events, and race.Results:Thirteen eligible studies involving 14,239 patients with CYP2C19*17 carriers or noncarriers were included in the meta-analysis. CYP2C19*17 was significantly related to decreased risk of major adverse cardiovascular and cerebrovascular events (MACCEs) in patients with coronary artery disease (CAD) (OR = 0.76, 95% CI: 0.60–0.98, P = 0.03), however, irrelevant with stent thrombosis in neither CAD nor ischemic heart disease patients. CYP2C19*17 was also significantly linked to decreased risk of high platelet reactivity (HPR) in CCVD patients (OR = 0.61, 95% CI: 0.43–0.88, P = 0.008). Meanwhile, CYP2C19*17 was significantly associated with bleeding risk in CCVD patients (OR = 1.89, 95% CI: 1.09–3.25, P = 0.02) but not related to major bleeding risk (OR = 1.35, 95% CI: 0.87–2.08, P = 0.18). Several outcomes in Caucasian subgroup were reverse to the overall results, such as bleeding events and HPR, which lacked significance.Conclusion:CYP2C19*17 had a significant effect on the reduced risks of MACCE and HPR as well as increased bleeding risk, but not on the risks of stent thrombosis and major bleeding in clopidogrel-treated CCVD patients. Outcomes might be different in different races.

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Clopidogrel, CYP2C19 and proton pump inhibitors: What we know and what it means

Cited by 9 publications

References 39 publications

Prevalence and Risk Factors of Potential Drug Interactions in Hospitalized Cardiovascular Patients Using Three Knowledge Bases

Prevalence and Risk Factors of Potential Drug Interactions in Hospitalized Cardiovascular Patients Using Three Knowledge Bases

Metabolic Interaction Potential between Clopidogrel and Sulfonylurea Antidiabetic Agents: Effects on Clopidogrel Bioactivation

Effect of cytochrome P450 2C19*17 allelic variant on cardiovascular and cerebrovascular outcomes in clopidogrel-treated patients: A systematic review and meta-analysis

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