title: Unbound liver concentration is the true inhibitor concentration that determines cytochrome P450-mediated drug-drug interactions in rat liver.
abstract: 1. In order to identify the best inhibitor concentration for the accurate prediction of magnitude of a hepatic cytochrome P450 (CYP)-mediated drug-drug interaction (DDI), the DDI between nifedipine, the CYP substrate probe, and fluconazole, ketoconazole, or ritonavir, the CYP inhibitors, in in situ rat liver perfusion system and rats were investigated. 2. In in situ system, the intrinsic clearance (CLint) of nifedipine was decreased after co-infusion of the CYP inhibitors. The decrease in in situ CLint of nifedipine was most comparable to that in in vitro CLint in rat liver microsomes calculated by using the unbound liver concentrations of inhibitors ([I]liver,u). The ratios of unbound liver concentration to unbound hepatic vein concentration (Kp,uu) of ketoconazole and ritonavir were 4.0-8.0 and 18.4-21.1, suggesting a concentrative uptake of them into liver. 3. In rats, the DDI effects of orally administered nifedipine with constant infusion of the inhibitors were investigated. The most accurate prediction of magnitude of DDI was achieved when [I]liver,u was applied as the inhibitor concentration. 4. These results indicated that [I]liver,u is the most reliable inhibitor concentration for CYP-mediated DDI and it is necessary to consider the concentrative uptake of inhibitors into liver for the quantitative prediction of DDI.
authors.affiliation: a Pharmaceutical Research Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Iwasaki
authors.affiliation: a Pharmaceutical Research Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirabayashi
authors.affiliation: a Pharmaceutical Research Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.affiliation: a Pharmaceutical Research Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited , Fujisawa , Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
mesh_terms: D000818:Animals; D019540:Area Under Curve; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology*; D015725:Fluconazole; D007654:Ketoconazole; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D015725:Fluconazole; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole
keywords: Fluconazole; in situ rat liver perfusion; intrinsic clearance (CLint); ketoconazole; nifedipine; ratio of unbound liver concentration to unbound hepatic vein concentration (Kp,uu); ritonavir