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Research ArticleArticle

Identification of Human Sulfotransferases Involved in Lorcaserin N-Sulfamate Formation

Abu J. M. Sadeque, Safet Palamar, Khawja A. Usmani, Chuan Chen, Matthew A. Cerny and Weichao G. Chen
Drug Metabolism and Disposition April 2016, 44 (4) 570-575; DOI: https://doi.org/10.1124/dmd.115.067397
Abu J. M. Sadeque
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Safet Palamar
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Khawja A. Usmani
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Chuan Chen
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Matthew A. Cerny
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Weichao G. Chen
Department of Drug Metabolism and Pharmacokinetics, Arena Pharmaceuticals, Inc., San Diego, California
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Abstract

Lorcaserin [(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine] hydrochloride hemihydrate, a selective serotonin 5-hydroxytryptamine (5-HT) 5-HT2C receptor agonist, is approved by the U.S. Food and Drug Administration for chronic weight management. Lorcaserin is primarily cleared by metabolism, which involves multiple enzyme systems with various metabolic pathways in humans. The major circulating metabolite is lorcaserin N-sulfamate. Both human liver and renal cytosols catalyze the formation of lorcaserin N-sulfamate, where the liver cytosol showed a higher catalytic efficiency than renal cytosol. Human sulfotransferases (SULTs) SULT1A1, SULT1A2, SULT1E1, and SULT2A1 are involved in the formation of lorcaserin N-sulfamate. The catalytic efficiency of these SULTs for lorcaserin N-sulfamate formation is widely variable, and among the SULT isoforms SULT1A1 was the most efficient. The order of intrinsic clearance for lorcaserin N-sulfamate is SULT1A1 > SULT2A1 > SULT1A2 > SULT1E1. Inhibitory effects of lorcaserin N-sulfamate on major human cytochrome P450 (P450) enzymes were not observed or minimal. Lorcaserin N-sulfamate binds to human plasma protein with high affinity (i.e., >99%). Thus, despite being the major circulating metabolite, the level of free lorcaserin N-sulfamate would be minimal at a lorcaserin therapeutic dose and unlikely be sufficient to cause drug-drug interactions. Considering its formation kinetic parameters, high plasma protein binding affinity, minimal P450 inhibition or induction potential, and stability, the potential for metabolic drug-drug interaction or toxicological effects of lorcaserin N-sulfamate is remote in a normal patient population.

Footnotes

    • Received September 30, 2015.
    • Accepted January 7, 2016.
  • ↵1 Current affiliation: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, East Hanover, New Jersey.

  • ↵2 Current affiliation: Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut.

  • ↵3 Current affiliation: Drug Metabolism & Pharmacokinetics, Vertex Pharmaceuticals, San Diego, California.

  • * Trade Name of Lorcaserin hydrochloride hemihydrate is BELVIQ.

  • dx.doi.org/10.1124/dmd.115.067397.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (4)
Drug Metabolism and Disposition
Vol. 44, Issue 4
1 Apr 2016
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Research ArticleArticle

Human Sulfotransferases Involved in Lorcaserin Metabolism

Abu J. M. Sadeque, Safet Palamar, Khawja A. Usmani, Chuan Chen, Matthew A. Cerny and Weichao G. Chen
Drug Metabolism and Disposition April 1, 2016, 44 (4) 570-575; DOI: https://doi.org/10.1124/dmd.115.067397

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Research ArticleArticle

Human Sulfotransferases Involved in Lorcaserin Metabolism

Abu J. M. Sadeque, Safet Palamar, Khawja A. Usmani, Chuan Chen, Matthew A. Cerny and Weichao G. Chen
Drug Metabolism and Disposition April 1, 2016, 44 (4) 570-575; DOI: https://doi.org/10.1124/dmd.115.067397
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