B01AC04 - Clopidogrel |
Propably not porphyrinogenic |
PNP |
Side effects
Common side effects are diarrhea and abdominal pain.
Rationale
Clopidogrel or its metabolites are not inducers or mechanism-based inhibitors of the quantitatively major CYP isoenzymes in the liver (i.e. CYP 3A4/5, CYP 2C9 and CYP 1A2). Clopidogrel is a mechanism-based inhibitor of CYP 2B6 and a metabolite of clopidogrel is a mechanism-based inhibitor of CYP 2C8.The amount of CYP 2C8 and 2B6 in the liver is relatively low and the de novo synthesis of these enzymes secondary to the mechanism-based inhibition is therefore limited and will not lead to a significant upregulation in the heme biosynthesis via ALAS-1.
Chemical description
Alpha amino acid ester
Therapeutic characteristics
Clopidogrel is a platelet aggregation inhibitor indicated for the prevention of atherothrombotic events (myocardial infarction, stroke and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease.
Clopidogrel has a half-life of 6 hours.
Metabolism and pharmakokinetics
Clopidogrel is a prodrug and the active metabolite is formed primarily by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6, CYP2C9 and CYP3A4 (Jiang 2015).
Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel (SPC).
Clopidogrel is found to be a mechanism-based inhibitor of CYP 2B6 (strong) and of CYP 2C19 (weak) (Richter 2004). The inhibition of CYP 2B6 have shown to cause clinically relevant drug-drug interactions with CYP 2B6 substrates (Turpeinen 2005).
The glucuronide metabolite clopidogrel acyl-β-D-glucuronide is a mechanism-based inhibitor of CYP 2C8 (Tornio 2014).
CYP2C8 accounts for 5% ( Pelkonen 2008) or 7% (Aquilante 2013) of the total CYP content in the liver, while the content of CYP 2B6 is reported to vary from 2% to 10% (Wang 2008) and below 5% (Pelkonen 2008).
IPNet drug reports
Uneventful use reported in 9 patients with acute porphyria.
References
- Scientific articles
- Tornio A, Filppula AM et al Glucuronidation converts clopidogrel to a strong time-dependent inhibitor of CYP2C8: a phase II metabolite as a perpetrator of drug-drug interactions. Clin Pharmacol Ther. 2014 Oct;96(4):498-507. #1165
- Turpeinen M, Tolonen A, Effect of clopidogrel and ticlopidine on cytochrome P450 2B6 activity as measured by bupropion hydroxylation. Clin Pharmacol Ther. 2005 Jun;77(6):553-9. PMID 15961986. #4368
- Aquilante CL, Niemi M et al. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 8. Pharmacogenet Genomics. 2013 Dec;23(12):721-8. PMID 23962911. #1158
- Jiang XL, Samant S et al. Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet. 2015 Feb;54(2):147-66. #3274
- Nishiya Y, Hagihara K, et al. Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab Dispos. 2009 Mar;37(3):589-93. PMID 19047469. #4367
- Pelkonen O, Turpeinen M et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008 Oct;82(10):667-715. PMID 18618097. #1082
- Richter T, Mürdter TE et al. Potent mechanism-based inhibition of human CYP2B6 by clopidogrel and ticlopidine. J Pharmacol Exp Ther. 2004 Jan;308(1):189-97. #1163
- Wang H, Tompkins LM. CYP2B6: new insights into a historically overlooked cytochrome P450 isozyme Curr Drug Metab. 2008 Sep;9(7):598-610. PMID 18781911. #1167
- Summary of Product Characteristics
- The electronic Medicines Compendium (emc). Summary of Product Characteristics (SPC). Plavix. #1164
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