Arzneimittelinteraktionen mit P2Y12-Antagonisten – Pharmakokinetische Grundlagen und Konsequenzen für die Praxis

Zusammenfassung

Pharmakokinetische Arzneimittelinteraktionen, die über CYP3A4 und / oder P-gp vermittelt werden, betreffen im Rahmen der antithrombotischen Therapie nicht nur die neuen direkten oralen Antikoagulanzien, sondern auch die wichtigen Thrombozytenaggregationshemmer vom Typ der P2Y12-Antagonisten. Hierbei sollen Kenntnisse über die hier dargestellten Grundlagen und Beispiele dem Kliniker eine Basis für rationale Therapieentscheidungen beim Einsatz der P2Y12-Antagonisten liefern.

Summary

Pharmacokinetic drug interactions that are mediated by CYP3A4 and/or P-gp, have an influence within the framework of antithrombotic therapy not only on the new direct oral anticoagulants but also on the important platelet aggregation inhibitors of the P2Y12 antagonists type. In such cases the here presented knowledge about their basic principles of action and examples is intended to provide the clinician with the foundations for rational therapeutic decisions on the use of the P2Y12 antagonists.

Key words

Drug interactions - P2Y12 antagonists - CYP3A4 - P-gp - antithrombotic therapy - new direct oral anticoagulants (DOAC) - platelet aggregation inhibitors

• Literatur

• 1 Kreutz R. Pharmakologie neuer oraler Antikoagulantien. Grundlage für rationale Entscheidungen. Klinikarzt 2012; 41 (S1): 10-15
• 2 Liu J, Sridhar J, Foroozesh M. Cytochrome P450 family 1 inhibitors and structure-activity relationships. Molecules 2013; 18: 14470-14495
• 3 Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005; 352: 2211-2221
• 4 Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976; 455: 152-162
• 5 Wessler JD, Grip LT, Mendell J, Giugliano RP. The P-glycoprotein transport system and cardiovascular drugs. J Am Coll Cardiol 2013; 61: 2495-2502
• 6 Miyamoto KI, Koga-Takeda K, Koga K et al. Saturable function of P-glycoprotein as a drug-efflux pump in multidrug-resistant tumour cells. J Pharm Pharmacol 1996; 48: 522-525
• 7 Lin JH. Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin Drug Metab Toxicol 2007; 3: 81-92
• 8 Cummins CL, Jacobsen W, Benet LZ. Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J. Pharmacol Exp Ther 2002; 300: 1036-1045
• 9 Ferri N, Corsini A, Bellosta S. Pharmacology of the new P2Y12 receptor inhibitors: insights on pharmacokinetic and pharmacodynamic properties. Drugs 2013; 73: 1681-1709
• 10 Tirkkonen T, Heikkila P, Vahlberg T et al. Epidemiology of CYP3A4-mediated clopidogrel drug-drug interactions and their clinical consequences. Cardiovasc Ther 2013; 31: 344-351
• 11 Fachinformation Clopidogrel. Stand 09/2013. http://www.fachinfo.de Letzter Zugriff 13.08.2014
• 12 Hulot JS, Collet JP, Montalescot G. Thienopyridine-associated drug-drug interactions: pharmacologic mechanisms and clinical relevance. Curr Cardiol Rep 2011; 13: 451-458
• 13 Farid NA, Payne CD, Small DS et al. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther 2007; 81: 735-741
• 14 Judge HM, Patil SB, Buckland RJ et al. Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation after clopidogrel. J Thromb Haemost 2010; 8: 1820-1827
• 15 Taubert D, von Beckerath N, Grimberg G et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501
• 16 Mega JL, Close SL, Wiviott SD et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet 2010; 376: 1312-1319
• 17 Jakubowski JA, Winters KJ, Naganuma H, Wallentin L. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 2007; 25: 357-374
• 18 Rehmel JL, Eckstein JA, Farid NA et al. Interactions of two major metabolites of prasugrel, a thienopyridine antiplatelet agent, with the cytochromes P450. Drug Metab Dispos 2006; 34: 600-607
• 19 Small DS, Farid NA, Payne CD et al. Effect of intrinsic and extrinsic factors on the clinical pharmacokinetics and pharmacodynamics of prasugrel. Clin Pharmacokinet 2010; 49: 777-798
• 20 Teng R, Oliver S, Hayes MA, Butler K. Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects. Drug Metab Dispos 2010; 38: 1514-1521
• 21 Fachinformation Ticagrelor. Stand 11/2013. http://www.fachinfo.de Letzter Zugriff 13.08.2014
• 22 Teng R, Mitchell P, Butler K. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects. Eur J Clin Pharmacol 2013; 69: 877-883