Identification of Human Cytochrome P450 and Flavin-Containing Monooxygenase Enzymes Involved in the Metabolism of Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine 2C Agonist

Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cyto-chrome P450 (P450) and flavin-containing monooxygenase (FMO) enzymes, was examined in vitro to identify the enzymes involved in the generation of its primary oxidative metabolites, N-hydroxylorca-serin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorca-serin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorca-serin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorca-serin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hy-droxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation ofN-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6