Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas ticlopidine and clopidogrel are metabolized to their thiolactones in the liver by cytochromes P450, prasugrel proceeds to its thiolactone following hydrolysis by carboxylesterase 2 during absorption, and a portion of prasugrel's active metabolite is also formed by intestinal CYP3A. Both ticlopidine and clopidogrel are subject to major competing metabolic pathways to inactive metabolites. Thus, varying efficiencies in the formation of active metabolites affect observed effects on the onset of action and extent of inhibition of platelet aggregation (IPA). Knowledge of the CYP-dependent formation of ticlopidine and clopidogrel thiolactones helps explain some of the observed drug-drug interactions with these molecules and, more important, the role of CYP2C19 genetic polymorphism on the pharmacokinetics of and pharmacodynamic response to clopidogrel. The lack of drug interaction potential and the absence of CYP2C19 genetic effect result in a predictable response to thienopyridine antiplatelet therapy with prasugrel. Current literature shows that greater ADP-mediated IPA is associated with significantly better clinical outcomes for patients with acute coronary syndrome.

Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans.

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.

https://www.dovepress.com/getfile.php?fileID=24229

Pharmacokinetic drug interactions with clopidogrel: updated review and risk management in combination therapy

Objective: To review potential drug interactions between antiretroviral (ARV) medications and antiplatelets or novel oral anticoagulants (NOACs). Data Sources: A literature search of MEDLINE, PubMed, EMBASE, International Pharmaceutical Abstracts, and Google Scholar was performed using the search terms (1) clopidogrel or ticagrelor or prasugrel, (2) dabigatran or rivaroxaban or apixaban, and (3) antiretrovirals. Study Selection and Data Extraction: Any English language study or case report describing a drug interaction between an ARV and an antiplatelet or NOAC was included. Additional information was taken from pharmacokinetic studies of individual agents alone or information from similar drug interactions. Results: Two studies were identified through the literature search: one reporting an in vivo interaction between ritonavir and prasugrel and the other an in vitro interaction between efavirenz and clopidogrel. A case report describing a drug interaction between nevirapine and rivaroxaban was also loca...

Drug Interactions Between Antiplatelet or Novel Oral Anticoagulant Medications and Antiretroviral Medications

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.12445

Clinical implications of drug-drug interactions with P2Y12 receptor inhibitors.

Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naive patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug–drug interaction liability.

Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists

Objective: Prasugrel is a thienopyridine antiplatelet agent for the prevention of atherothrombotic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Since cytochrome P450 enzymes CYP3A4 and CYP2B6 play a major role in prasugrel's active metabolite formation, the effect of potent CYP induction by rifampin on the pharmacokinetics of prasugrel and on the pharmacodynamic response to prasugrel was evaluated in healthy male subjects.Research design and methods: This was an open-label, two-period, fixed-sequence study conducted at a single clinical research center. In the first treatment period, subjects received prasugrel as an oral 60-mg loading dose (LD) on the first day followed by ten oral, 10-mg daily maintenance doses. After a 2-week washout period, subjects received oral rifampin alone (600 mg once daily) for 8 days, followed by coadministration of oral rifampin with prasugrel, given as a 60-mg LD on the first day followed by five daily 10-mg MDs. Bloo...

Effect of rifampin on the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects

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Effect of rifampin on the pharmacokinetics and pharmacodynamics of prasugrel in healthy male subjects