title: The role of P-glycoprotein in the pharmacokinetics and tissue distribution of a hepatitis C virus protease inhibitor.
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 P-glycoprotein (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.
authors.affiliation: Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Chen
authors.forename: Bancha
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: Tongtong
authors.initials: T
authors.lastname: Liu
authors.forename: Lisa
authors.initials: L
authors.lastname: Broske
authors.forename: Genfeng
authors.initials: G
authors.lastname: Wang
authors.forename: Cheng
authors.initials: C
authors.lastname: Li
authors.forename: F George
authors.initials: FG
authors.lastname: Njoroge
authors.forename: Annette S
authors.initials: AS
authors.lastname: Uss
authors.forename: K-C
authors.initials: KC
authors.lastname: Cheng
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D016174:Hepacivirus / Q000201:enzymology*; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011480:Protease Inhibitors