ABSTRACT
PURPOSE: The objective of this study was to examine the metabolism and disposition of the HIV protease inhibitor lopinavir in humans and animal models. METHODS: The plasma protein binding of [14C]lopinavir was examined in vitro via equilibrium dialysis technique. The tissue distribution of radioactivity was examined in rats dosed with [14C]lopinavir in combination with ritonavir. The metabolism and disposition of [14C]lopinavir was examined in rats, dogs, and humans given alone (in rats only) or in combination with ritonavir. RESULTS: The plasma protein binding of lopinavir was high in all species (97.4-99.7% in human plasma), with a concentration-dependent decrease in binding. Radioactivity was extensively distributed into tissues, except brain, in rats. On oral dosing to rats, ritonavir was found to increase the exposure of lopinavir-derived radioactivity 13-fold. Radioactivity was primarily cleared via the hepato-biliary route in all species (>82% of radioactive dose excreted via fecal route), with urinary route of elimination being significant only in humans (10.4% of radioactive dose). Oxidative metabolites were the predominant components of excreted radioactivity. The predominant site of metabolism was found to be the carbon-4 of the cyclic urea moiety, with subsequent secondary metabolism occurring on the diphenyl core moiety. In all the three species examined, the primary component of plasma radioactivity was unchanged lopinavir (>88%) with small amounts of oxidative metabolites. CONCLUSIONS: Lopinavir was subject to extensive metabolism in vivo. Co-administered ritonavir markedly enhanced the pharmacokinetics of lopinavir-derived radioactivity in rats, probably due to inhibition of presystemic and systemic metabolism, leading to an increased exposure to this potent HIV protease inhibitor.
Subject(s)
HIV Protease Inhibitors/pharmacokinetics , Pyrimidinones/pharmacokinetics , Ritonavir/pharmacokinetics , Administration, Oral , Adult , Animals , Bile/metabolism , Blood Proteins/metabolism , Dogs , Drug Combinations , Feces/chemistry , Female , HIV Protease Inhibitors/administration & dosage , Humans , Injections, Intravenous , Lopinavir , Macaca fascicularis , Male , Models, Chemical , Molecular Structure , Protein Binding , Pyrimidinones/administration & dosage , Pyrimidinones/chemistry , Rats , Rats, Sprague-Dawley , Ritonavir/administration & dosage , Tissue DistributionABSTRACT
In search of a novel chemotype of K(ATP) channel openers a series of tricyclic dihydropyridopyrazolones and dihydropyridoisoxazolones was synthesized. It was found that cyclopentanone in the left hand portion of the molecule was 4-fold more potent than cyclohexanone. Introduction of gem-dimethyl groups as well as incorporation of oxygen in the cyclohexanone ring in the left hand portion of the molecule increased the potency 10-fold. In the right hand portion of the molecule, the NH-group of the pyrazolone can be effectively substituted by oxygen increasing the activity 5-fold. Incorporation of a methyl group adjacent to the dihydropyridine (DHP) nitrogen not only significantly boosted activity, but also provided an additional benefit of increased metabolic stability. In vitro tests on the tissue from pig bladder strips provided further confirmation of K(ATP) activity of these compounds.
