title: Organic anion transporting polypeptide-mediated transport of, and inhibition by, asunaprevir, an inhibitor of hepatitis C virus NS3 protease.
abstract: Asunaprevir (ASV), an investigational, highly protein-bound inhibitor of hepatitis C virus NS3 protease, shows considerable hepatic compartmentalization in animal models. Preclinical data showed ASV inhibition of human OATP1B1 (IC50 = 0.3 μM), OATP2B1 (0.27 μM), and, to a lesser extent OATP1B3 (3.0 μM), confirmed by modest (<2-fold) clinical elevations in rosuvastatin exposure with concomitant ASV. Although no significant OATP transport of ASV was observed in vitro at standard micromolar assay concentrations, clinical coadministration of ASV with a single dose of the OATP inhibitor rifampin gave large, variable increases in ASV plasma Cmax (21-fold mean) and AUCinf (15-fold mean), consistent with reduced hepatic uptake. In vitro reevaluation at therapeutically relevant low-nanomolar concentrations of unbound ASV showed active, saturable human hepatocyte uptake (Km = 0.685 μM) and rifampin-reversible transport by OATP1B1 and OATP2B1, but not OATP1B3. At therapeutically relevant concentrations, ASV is therefore a sensitive substrate for, and weak inhibitor of, human OATP1B1, 1B3 and 2B1.
authors: Bristol-Myers Squibb, Research and Development, Princeton, New Jersey, USA.
authors: T
authors: T
authors: Eley
authors: Y-H
authors: YH
authors: Han
authors: S-P
authors: SP
authors: Huang
authors: B
authors: B
authors: He
authors: W
authors: W
authors: Li
authors: W
authors: W
authors: Bedford
authors: M
authors: M
authors: Stonier
authors: D
authors: D
authors: Gardiner
authors: K
authors: K
authors: Sims
authors: A D
authors: AD
authors: Rodrigues
authors: R J
authors: RJ
authors: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005464:Fluorobenzenes / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D009865:Oocytes / Q000187:drug effects; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000378:metabolism; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000378:metabolism* / Q000494:pharmacology*; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D005464:Fluorobenzenes; D007546:Isoquinolines; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; C571889:asunaprevir; D012293:Rifampin