Metabolism of quinoline 3-carboxamide compounds, a group of synthetic immunomodulators, in various species

Detta är en avhandling från Helen Tuvesson, Active Biotech Research AB, Box 724, 221 07 Lund

Sammanfattning: Cytochrome P450 (CYP) is involved in the metabolism of the majority of clinically used drugs. We have studied the CYP mediated metabolism of quinoline 3-carboxamides, a group of synthetic immunomodulators in liver microsomal preparations from various species. Roquinimex, the lead compound, was found to be metabolised by CYPs to hydroxylated and demethylated metabolites. A similar metabolite pattern was demonstrated in liver microsomes from species used for the pharmacological and toxicological evaluation as well as from man. In human enzymatic systems, CYP3A4 was determined to catalyse the primary metabolism. When projecting in vitro metabolism data to in vivo pharmacokinetics a good correlation was obtained. Thus, the CYP metabolism seems to be a major determinant of the pharmacokinetics of roquinimex in vivo. Metabolism and pharmacokinetics of 5-substituted quinoline based compounds have been evaluated. Generally similar metabolite patterns were formed in different species. Introduction of a substituent in the 5-position seemed to affect the metabolite pattern e.g. a preference for dealkylation at the carboxamide position as compared to roquinimex. Replacing the methyl at the carboxamide position with an ethyl group results in pronounced hydroxylation in the quinoline moiety. The enzyme kinetics was affected by introduction of an ethyl group; lower KM values, higher CLInt , and higher clearance was determined both in vitro and in vivo. When comparing metabolism data with in vivo pharmacokinetics in the mouse, a relationship between systemic exposure of parent compound and disease inhibitory effects was seen. We show that laquinimod, currently in phase II clinical trials, is metabolised by CYP3A4 and potent CYP3A4 inhibitors such as ketoconazole may affect laquinimod pharmacokinetics. Keywords: Metabolism, cytochrome P450, quinoline 3-carboxamides, enzyme kinetics, pharmacokinetics

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