B01AC22 - Prasugrel |
Propably not porphyrinogenic |
PNP |
Rationale
The prodrug prasugrel is rapidly hydrolysed to a thiolactione in the intestines. The thiolactone metabolite is a substrate of CYP3A4, CYP2B6, CYP2C9 and CYP2C19. There are no in vitro or in vivo data indicating that prasugrel inhibits or induce the major CYP enzymes.
Therapeutic characteristics
Prasugrel is indicated for prevention of atherotrombotic incidences in patients with acute coronary syndromes subjected to percutaneous coronary intervention. Administration to patients >75 years is generally not recommended.
Hepatic exposure
Probably significant hepatic exposure with regard to the active thiolactone metabolite.
Metabolism and pharmakokinetics
Prasugrel is a prodrug which is rapidly hydrolysed in the intestines to a thiolactone by human carboxylesterase 2 (Laizure 2010). The thiolactone is converted by CYP3A4, CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19, to the active metabolite which is inactivated after S-metylation and conjugation with cysteine (Schrör 2011, Small 2010).
In vitro studies have shown that it is unlikely that the main metabolites of prasugrel will inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Small 2010). Other in vitro data however, showed that the metabolite R-95913 inhibits CYP2C9, CYP2C19, CYP2D6 and CYP3A4. The data also indicated that the inhibitions best fit the competitive inhibition model, except for CYP2D6 which best fitted the non-competitive inhibition model (Rehmel 2006).
In vitro studies have shown that prasugrel and its thiolactone metabolite R-95913 are mechanism-based inhibitors of CYP2B6, but have no potential to be a mechanism-based inhibitor of CYP2C19 (Nishiya 2009). In clinical use prasugrel does not inhibit CYP2C9, but is a weak inhibitor of CYP2B6 (Small 2010, Farid 2008). Unlike clopidogrel, very few drug-drug interactions have been reported for prasugrel (hulot 2011) and there are no in vitro or in vivo data indicating that prasugrel inhibits or induces the major CYP enzymes.
References
- Scientific articles
- Farid NA, Payne CD, et al. Prasugrel, a new thienopyridine antiplatelet drug, weakly inhibits cytochrome P450 2B6 in humans. J Clin Pharmacol. 2008 Jan;48(1):53-9. PMID 18094219. #4729
- Laizure SC, Parker RB. A comparison of the metabolism of clopidogrel and prasugrel. Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1417-24. #3020
- Nishiya Y, Hagihara K, et al. Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine, clopidogrel, and prasugrel. Xenobiotica. 2009 Nov;39(11):836-43. PMID 19845434. #4730
- 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
- Rehmel JL, Eckstein JA, et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos. 2006 Apr;34(4):600-7. PMID 16415119. #4731
- Schrör K, Siller-Matula JM, Huber K. Pharmacokinetic basis of the antiplatelet action of prasugrel. Fundam Clin Pharmacol. 2012 Feb;26(1):39-46. PMID 21895761. #3022
- Small DS, Farid NA, et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clin Pharmacokinet. 2010 Dec;49(12):777-98. #3023
- Summary of Product Characteristics
- Norwegian medicines agency. Summary of Product Characteristics (SPC). prasugrel. #3019
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