Abstract
Lorcaserin, a selective serotonin 5-hydroxytryptamine 2C (5-HT)2C receptor agonist, is being developed for weight management. The oxidative metabolism of lorcaserin, mediated by recombinant human cytochrome 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-hydroxylorcaserin, 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin. Human CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6*1, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6*1 and CYP3A4 in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6*1, and CYP3A4 in 5-hydroxylorcaserin; and CYP3A4 in 1-hydroxylorcaserin formation. In sixteen individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin with CYP2D6, 5-hydroxylorcaserin with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin with CYP3A4 activity at 10 μM of lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1 μM of lorcaserin. N-Hydroxylorcaserin formation was not inhibited by CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2D6, and CYP3A4 inhibitors at the highest concentration tested. Furafylline, quinidine, and ketoconazole, selective inhibitors of CYP1A2, CYP2D6, and CYP3A4, respectively, inhibited 5-hydroxylorcaserin (IC50 = 1.914 μM), 7-hydroxylorcaserin (IC50 = 0.213 μM), and 1-hydroxylorcaserin formation (IC50 = 0.281 μM), respectively. N-Hydroxylorcaserin showed low and high Km components in HLM and 7-hydroxylorcaserin showed lower Km than 5-hydroxylorcaserin and 1-hydroxylorcaserin in HLM. The highest intrinsic clearance was observed for N-hydroxylorcaserin, followed by 7-hydroxylorcaserin, 5-hydroxylorcaserin, and 1-hydroxylorcaserin in HLM. Multiple human P450 and FMO enzymes catalyze formation of four primary oxidative metabolites of lorcaserin, suggesting lorcaserin has a low probability of drug-drug interactions by concomitant medications.
- cytochrome P450 catalyzed oxidations
- cytochrome P450 isoforms
- drug-drug interactions
- flavin-containing monooxygenase
- human CYP enzymes
- kinetics
- Received October 27, 2011.
- Accepted January 20, 2012.
- The American Society for Pharmacology and Experimental Therapeutics