Metabolism, Pharmacokinetics, and Excretion of Lorcaserin, a Novel Selective Serotonin 5-HT2C Receptor Agonist, in Healthy Male Volunteers

Abstract

Lorcaserin, (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride, a novel selective serotonin 5-HT2C receptor agonist, is currently under development for the treatment of obesity. Metabolism, pharmacokinetics, and excretion of [14C]lorcaserin were investigated in six healthy male volunteers following a single 10 mg oral dose (100 µCi). Plasma, urine and fecal samples were analyzed for mass balance and metabolite profiling. Mass balance of radioactivity was achieved. Drug-related material was primarily excreted in the urine (92.3% of dose), and only small amounts of administered radioactivity were excreted in the feces (2.2% of dose). The high percentage of urinary elimination of total radioactivity suggested that the primary elimination route for lorcaserin and its metabolites was renal; fecal elimination was not a major route of elimination. Lorcaserin was almost completely absorbed and rapidly reached its maximum concentration in plasma, with a Tmax of approximately 2 hours post dosing. The absorption profile is consistent with in vitro results demonstrating that lorcaserin is neither a substrate nor an inhibitor of the P-gp efflux transporter. The half-life of lorcaserin was approximately 11 hours. In addition to unchanged lorcaserin, metabolite M1, lorcaserin sulfamate, was identified as the major circulating metabolite, representing 38% of total radioactivity in the pooled plasma. N-carbamoyl glucuronide of lorcaserin was identified as the major metabolite in urine, and represented 36% of total administered dose. While lorcaserin sulfamate was the major metabolite in human plasma, it was only a minor metabolite in urine, representing approximately 3% of dose. Lorcaserin parent drug excreted in urine only represented a small percentage of dose (approximately 1%). Additional metabolites excreted in urine were identified as either glucuronide or sulfate conjugates of oxidative metabolites. These results suggest that lorcaserin is extensively metabolized through multiple pathways including N-carbamoyl glucuronidation, N-sulfonation and oxidation followed by phase II conjugation. Since the metabolism and disposition of lorcaserin is not dependent on any single metabolic pathway, lorcaserin is unlikely to be susceptible to drug-drug interactions caused by marketed drugs.