title: An integrated pharmacokinetic model for the influence of CYP3A4 expression on the in vivo disposition of lopinavir and its modulation by ritonavir.
abstract: Lopinavir, a human immunodeficiency virus protease inhibitor, has a very low oral bioavailability, which can be enhanced with a low dose of the CYPA4 inhibitor ritonavir. Our aim was to separately quantify the role of intestinal and hepatic cytochrome P450 3A (CYP3A4) expression on lopinavir disposition in a novel mouse model. Lopinavir and ritonavir were administered to mice selectively expressing human CYP3A4 in the intestine and/or liver. Using nonlinear mixed-effects modeling, we could separately quantify the effects of intestinal CYP3A4 expression, hepatic CYP3A4 expression, and the presence of ritonavir on both the absorption and elimination of lopinavir, which was previously not possible using noncompartmental methods. Intestinal, but not hepatic, CYP3A4-related first-pass metabolism was the major barrier for systemic entry of lopinavir. Relative oral bioavailability of lopinavir in mice expressing both hepatic and intestinal CYP3A4 was only 1.3% when compared with mice that were CYP3A deficient. In presence of ritonavir, relative bioavailability increased to 9.5% due to inhibiton of intestinal, but not due to inhibition of hepatic first-pass metabolism. Hepatic CYP3A4 related systemic clearance was inversely related to ritonavir exposure and not only hepatic but also intestinal CYP3A4 expression contributed to systemic clearance of lopinavir.
authors.affiliation: Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, the Netherlands. rob@terheine.nl
authors.forename: Rob
authors.initials: R
authors.lastname: ter Heine
authors.forename: Robert A B
authors.initials: RA
authors.lastname: Van Waterschoot
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Alfred H
authors.initials: AH
authors.lastname: Schinkel
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000818:Animals; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D004347:Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D061466:Lopinavir; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D012995:Solubility; D014018:Tissue Distribution
chemical_list: D017320:HIV Protease Inhibitors; D011744:Pyrimidinones; D061466:Lopinavir; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir