title: Hepatic Clearance Prediction of Nine Human Immunodeficiency Virus Protease Inhibitors in Rat.
abstract: This study aimed to determine the rate-limiting step in the overall hepatic clearance of the marketed human immunodeficiency virus (HIV) protease inhibitors (PI) in rats by predicting the experimentally determined hepatic in vivo clearance of these drugs based on in vitro clearance values for uptake and/or metabolism. In vitro uptake and metabolic clearance values were determined in suspended rat hepatocytes and rat liver microsomes, respectively. In vivo hepatic clearance was determined after intravenous bolus administration in rats. Excellent in vitro-in vivo correlation (IVIVC; R(2) = 0.80) was observed when metabolic intrinsic Cl values were used, which were determined in vitro at a single concentration corresponding to the blood concentration observed in rats in vivo at the mean residence time. On the contrary, poor IVIVC was observed when in vitro metabolic Cl values based on full Michaelis-Menten profiles were used. In addition, the use of uptake Cl values or a combination of both uptake and metabolic clearance data led to poor predictions of in vivo clearance. Although our findings indicate a key role for metabolism in the hepatic clearance of several HIV PI in rats, subsequent simulations revealed that inhibition of hepatic uptake can lead to altered hepatic clearance for several of these drugs.
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O&N2, Leuven 3000, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: De Bruyn
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O&N2, Leuven 3000, Belgium.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Augustijns
authors.affiliation: Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O&N2, Leuven 3000, Belgium. Electronic address: pieter.annaert@pharm.kuleuven.be.
authors.forename: Pieter P
authors.initials: PP
authors.lastname: Annaert
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005544:Forecasting; D017320:HIV Protease Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D017320:HIV Protease Inhibitors
keywords: HIV/AIDS; drug metabolizing enzymes; drug transport; hepatic clearance; hepatic metabolism; hepatic transport; in vitro/in vivo correlations (IVIVC); transporters