Organic Anion Transporting Polypeptide‐Mediated Transport of, and Inhibition by, Asunaprevir, an Inhibitor of Hepatitis C Virus NS3 Protease. Issue 2 (20th December 2014)

• Record Type: Journal Article
• Authors: Eley, T; Han, Y‐H; Huang, S‐P; He, B; Li, W; Bedford, W; Stonier, M; Gardiner, D; Sims, K; Rodrigues, AD; Bertz, RJ
• Is Part Of: Clinical pharmacology & therapeutics. Volume 97:Issue 2(2015:Feb.)
• Page Start: 159
• Page End: 166
• Publication Date: 2014-12-20
• Subjects: Pharmacology -- Periodicals; Therapeutics -- Periodicals; 615.5
• DOI: 10.1002/cpt.4
• Languages: English
• ISSNs: 0009-9236

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 (&lt;2‐fold) clinical elevations in rosuvastatin exposure with concomitant ASV. Although no significant OATP transport of ASV was observed <italic>in vitro</italic> 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 C_max (21‐fold mean) and AUC_inf (15‐fold mean), consistent with reduced hepatic uptake. <italic>In vitro</italic> reevaluation at therapeutically relevant low‐nanomolar concentrations of unbound ASV showed active, saturable human hepatocyte uptake (K_m = 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.</p> </abstract>