title: Ritonavir inhibits the two main prasugrel bioactivation pathways in vitro: a potential drug-drug interaction in HIV patients.
abstract: Prasugrel is an antiplatelet prodrug used in patients with acute coronary syndrome. Prasugrel is mainly bioactivated by cytochromes P450 3A4/5 and CYP2B6. HIV patients are at risk of cardiovascular disease, and the protease inhibitor ritonavir is a potent inhibitor of these 2 CYPs. The aim of this in vitro study was to determine the impact of ritonavir in prasugrel metabolism. Human liver microsomes (HLMs) and recombinant microsomes were used to identify the enzymes responsible for the bioactivation of prasugrel. Prasugrel concentrations of 5 to 200 μM were used for Km determination. Inhibition by ritonavir was characterized using HLMs at concentrations of 0.1 to 30 μM. Prasugrel active metabolite determination was performed with a validated liquid chromatography-mass spectrometry method. Using recombinant microsomes, prasugrel biotransformation was mainly performed by CYP2B6, CYP2D6, CYP2C19, CYP3A4, and CYP3A5. With specific inhibitors of CYP3A, CYP2B6, CYP2D6, CYP2C9, and CYP2C19, active metabolite production was decreased by 38% ± 15% with 4-(4-chlorobenzyl)pyridine (CYP2B6 inhibitor) and by 45 ± 16% with ketoconazole (CYP3A inhibitor). The Km value for prasugrel metabolism in HLMs was determined to be 92.5 μM. Ritonavir at 0.1 to 30 μM was shown to be a potent dose-dependent inhibitor of prasugrel. In this in-vitro study, we found a potent inhibition of prasugrel bioactivation by ritonavir compared to the specific inhibitors of CYP3A and CYP2B6 due to the simultaneous inhibition of CYP2B6 and CYP3A by ritonavir. This finding suggests a potential significant drug-drug interaction between these two drugs.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland. youssef.daali@hcuge.ch
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Virginie
authors.initials: V
authors.lastname: Ancrenaz
authors.forename: Marija
authors.initials: M
authors.lastname: Bosilkovska
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
mesh_terms: D016642:Bupropion / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D016642:Bupropion; D000068799:Prasugrel Hydrochloride; D019438:Ritonavir