Organic anion transporting polypeptide-mediated transport of, and inhibition by, asunaprevir, an inhibitor of hepatitis C virus NS3 protease.

Article Details

Citation

Eley T, Han YH, Huang SP, He B, Li W, Bedford W, Stonier M, Gardiner D, Sims K, Rodrigues AD, Bertz RJ

Organic anion transporting polypeptide-mediated transport of, and inhibition by, asunaprevir, an inhibitor of hepatitis C virus NS3 protease.

Clin Pharmacol Ther. 2015 Feb;97(2):159-66. doi: 10.1002/cpt.4. Epub 2014 Dec 20.

PubMed ID
25670521 [ View in PubMed
]
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 muM), OATP2B1 (0.27 muM), and, to a lesser extent OATP1B3 (3.0 muM), 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 muM) 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.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AsunaprevirSolute carrier organic anion transporter family member 1B1ProteinHumans
Unknown
Substrate
Inhibitor
Details
AsunaprevirSolute carrier organic anion transporter family member 1B3ProteinHumans
Unknown
Inhibitor
Details
AsunaprevirSolute carrier organic anion transporter family member 2B1ProteinHumans
Unknown
Substrate
Inhibitor
Details