Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1.
Article Details
- CitationCopy to clipboard
Polasek TM, Doogue MP, Miners JO
Metabolic activation of clopidogrel: in vitro data provide conflicting evidence for the contributions of CYP2C19 and PON1.
Ther Adv Drug Saf. 2011 Dec;2(6):253-61. doi: 10.1177/2042098611422559.
- PubMed ID
- 25083217 [ View in PubMed]
- Abstract
The recent report that clopidogrel efficacy may be more dependent on paraoxonase-1 (PON1) than on cytochrome P450 2C19 (CYP2C19) activity raises questions about the roles of these and other enzymes in clopidogrel activation. To provide insight into the emerging PON1 versus CYP2C19 debate, this commentary summarizes the clinical evidence on the pharmacokinetic determinants of clopidogrel efficacy. We then review the in vitro studies investigating the enzymes involved in clopidogrel activation, and comment on their strengths and limitations. There is agreement amongst in vitro studies regarding the involvement of CYP1A2 and CYP2B6 in the metabolism of clopidogrel to 2-oxo-clopidogrel. However, the evidence for other CYP enzymes in the first activation step (e.g. CYP2C19 and CYP3A4) is inconsistent and dependent on the in vitro test system and laboratory. All major drug metabolizing CYP enzymes are capable of converting 2-oxo-clopidogrel to sulfenic acid intermediates that subsequently form the active thiol metabolite. However, the extent of CYP involvement in this second step has been challenged, and new evidence suggests that CYP-independent hydrolytic cleavage of the thioester bond may be more important than oxidative metabolism.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Clopidogrel Cytochrome P450 1A2 Protein Humans NoSubstrateDetails