Ticagrelor Increases Exposure to the Breast Cancer Resistance Protein Substrate Rosuvastatin.

Autor: Lehtisalo M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Tarkiainen EK; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Neuvonen M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Holmberg M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Emergency Medicine and Services, Helsinki University Hospital, Helsinki, Finland., Kiiski JI; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Lapatto-Reiniluoto O; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Filppula AM; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Pharmaceutical Sciences Laboratory, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland., Kurkela M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland., Backman JT; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland., Niemi M; Department of Clinical Pharmacology, University of Helsinki, Helsinki, Finland.; Individualized Drug Therapy Research Program, University of Helsinki, Helsinki, Finland.; Department of Clinical Pharmacology, HUS Diagnostic Center, Helsinki University Hospital, Helsinki, Finland.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 Jan; Vol. 115 (1), pp. 71-79. Date of Electronic Publication: 2023 Oct 20.
DOI: 10.1002/cpt.3067
Abstrakt: Ticagrelor and rosuvastatin are often used concomitantly after atherothrombotic events. Several cases of rhabdomyolysis during concomitant ticagrelor and rosuvastatin have been reported, suggesting a drug-drug interaction. We showed recently that ticagrelor inhibits breast cancer resistance protein (BCRP) and organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1-mediated rosuvastatin transport in vitro. The aim of this study was to investigate the effects of ticagrelor on rosuvastatin pharmacokinetics in humans. In a randomized, crossover study, 9 healthy volunteers ingested a single dose of 90 mg ticagrelor or placebo, followed by a single 10 mg dose of rosuvastatin 1 hour later. Ticagrelor 90 mg or placebo were additionally administered 12, 24, and 36 hours after their first dose. Ticagrelor increased rosuvastatin area under the plasma concentration-time curve (AUC) and peak plasma concentration 2.6-fold (90% confidence intervals: 1.8-3.8 and 1.7-4.0, P = 0.001 and P = 0.003), and prolonged its half-life from 3.1 to 6.6 hours (P = 0.009). Ticagrelor also decreased the renal clearance of rosuvastatin by 11% (3%-19%, P = 0.032). The N-desmethylrosuvastatin:rosuvastatin AUC 0-10h ratio remained unaffected by ticagrelor. Ticagrelor had no effect on the plasma concentrations of the endogenous OATP1B substrates glycodeoxycholate 3-O-glucuronide, glycochenodeoxycholate 3-O-glucuronide, glycodeoxycholate 3-O-sulfate, and glycochenodeoxycholate 3-O-sulfate, or the sodium-taurocholate cotransporting polypeptide substrate taurocholic acid. These data indicate that ticagrelor increases rosuvastatin concentrations more than twofold in humans, probably mainly by inhibiting intestinal BCRP. Because the risk for rosuvastatin-induced myotoxicity increases along with rosuvastatin plasma concentrations, using ticagrelor concomitantly with high doses of rosuvastatin should be avoided.
(© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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