The Role of P-Glycoprotein in the Pharmacokinetics and Tissue Distribution of a Hepatitis C Virus Protease Inhibitor

Kevin   X.   Chen; Bancha      Vibulbhan; Tongtong      Liu; Lisa      Broske; Genfeng      Wang; Cheng      Li; F.   George   Njoroge; Annette   S.   Uss; K.-C.      Cheng

Abstract

S5, a hepatitis C virus protease inhibitor, displays partially saturable efflux in the Caco-2 system. In addition, the efflux can be reversed by cyclosporine, indicating that S5 may be a human Pglycoprotein (P-gp) substrate. S5 can also activate the ATPase activity in vesicle membranes containing mouse P-gp 1a and 1b, suggesting that S5 may be a substrate for mouse P-gp. The pharmacokinetics and tissue distribution of S5 were evaluated after intravenous and oral administration to wild-type and 1a/1b knockout mice. Plasma and kidney levels of this compound in knockout mice were transiently higher than those in wild-type mice only after oral dosing, indicating effective P-gp efflux occurs in wild-type mice. The levels of S5 in brain samples from knockout mice were higher than those from wild-type mice after both intravenous and oral administration, but much more significantly after intravenous administration. The levels in liver were four time higher in knockout mice than in wild-type mice after oral administration, but were not different between knockout and wild-type mice after intravenous administration. These results suggest that P-gp efflux limits exposure to S5 in the brain and liver, and that the effect is dependent on the route of administration.

Keywords: P-glycoprotein, P-gp knockout mice, HCV protease inhibitor, tissue distribution, pharmacokinetics

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