title: Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy.
abstract: BACKGROUND
  Coprescribing of clopidogrel and other drugs is common. Available reviews have addressed the drug-drug interactions (DDIs) when clopidogrel is as an object drug, or focused on combination use of clopidogrel and a special class of drugs. Clinicians may still be ignorant of those DDIs when clopidogrel is a precipitant drug, the factors determining the degree of DDIs, and corresponding risk management.
  
  
  METHODS
  A literature search was performed using PubMed, MEDLINE, Web of Science, and the Cochrane Library to analyze the pharmacokinetic DDIs of clopidogrel and new P2Y12 receptor inhibitors.
  
  
  RESULTS
  Clopidogrel affects the pharmacokinetics of cerivastatin, repaglinide, ferulic acid, sibutramine, efavirenz, and omeprazole. Low efficacy of clopidogrel is anticipated in the presence of omeprazole, esomeprazole, morphine, grapefruit juice, scutellarin, fluoxetine, azole antifungals, calcium channel blockers, sulfonylureas, and ritonavir. Augmented antiplatelet effects are anticipated when clopidogrel is coprescribed with aspirin, curcumin, cyclosporin, St John's wort, rifampicin, and angiotensin-converting enzyme inhibitors. The factors determining the degree of DDIs with clopidogrel include genetic status (eg, cytochrome P540 [CYP]2B6*6, CYP2C19 polymorphism, CYP3A5*3, CYP3A4*1G, and CYP1A2-163C.A), species differences, and dose strength. The DDI risk does not exhibit a class effect, eg, the effects of clopidogrel on cerivastatin versus other statins, the effects of proton pump inhibitors on clopidogrel (omeprazole, esomeprazole versus pantoprazole, rabeprazole), the effects of rifampicin on clopidogrel versus ticagrelor and prasugrel, and the effects of calcium channel blockers on clopidogrel (amlodipine versus P-glycoprotein-inhibiting calcium channel blockers). The mechanism of the DDIs with clopidogrel involves modulating CYP enzymes (eg, CYP2B6, CYP2C8, CYP2C19, and CYP3A4), paraoxonase-1, hepatic carboxylesterase 1, P-glycoprotein, and organic anion transporter family member 1B1.
  
  
  CONCLUSIONS
  Effective and safe clopidogrel combination therapy can be achieved by increasing the awareness of potential changes in efficacy and toxicity, rationally selecting alternatives, tailoring drug therapy based on genotype, checking the appropriateness of physician orders, and performing therapeutic monitoring.
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: VIP Care Ward, Division of Nursing, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Lu-Shan
authors.initials: LS
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Su
authors.initials: S
authors.lastname: Zeng
authors.affiliation: Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Mei-Xiang
authors.initials: MX
authors.lastname: Xiang
authors.affiliation: Department of Pharmacy, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
keywords: P2Y12 receptor inhibitors; clopidogrel; drug metabolism; drug transporter; drug–drug interactions; genotype; pharmacogenetics; pharmacokinetics; polypharmacy; risk management
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