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Research ArticleArticle

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

Khawja A. Usmani, Weichao G. Chen and Abu J.M. Sadeque
Drug Metabolism and Disposition April 2012, 40 (4) 761-771; DOI: https://doi.org/10.1124/dmd.111.043414
Khawja A. Usmani
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Weichao G. Chen
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Abu J.M. Sadeque
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Abstract

Lorcaserin, a selective serotonin 5-hydroxytryptamine 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, CYP3A4, and FMO1 are major enzymes involved in N-hydroxylorcaserin; CYP2D6 and CYP3A4 are enzymes involved in 7-hydroxylorcaserin; CYP1A1, CYP1A2, CYP2D6, and CYP3A4 are enzymes involved in 5-hydroxylorcaserin; and CYP3A4 is an enzyme involved in 1-hydroxylorcaserin formation. In 16 individual human liver microsomal preparations (HLM), formation of N-hydroxylorcaserin was correlated with CYP2B6, 7-hydroxylorcaserin was correlated with CYP2D6, 5-hydroxylorcaserin was correlated with CYP1A2 and CYP3A4, and 1-hydroxylorcaserin was correlated with CYP3A4 activity at 10.0 μM lorcaserin. No correlation was observed for N-hydroxylorcaserin with any P450 marker substrate activity at 1.0 μM 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 the formation of four primary oxidative metabolites of lorcaserin, suggesting that lorcaserin has a low probability of drug-drug interactions by concomitant medications.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.043414.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    1-ABT
    1-aminobenzotriazole
    HLM
    human liver microsomes
    HRM
    human renal microsomes
    FMO
    flavin-containing monooxygenase
    LC-MS/MS
    liquid chromatography/tandem mass spectrometry
    %TNR
    total normalized rates
    FAD
    flavin adenine dinucleotide.

  • Received October 19, 2011.
  • Accepted January 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (4)
Drug Metabolism and Disposition
Vol. 40, Issue 4
1 Apr 2012
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Research ArticleArticle

HUMAN P450 AND FMO INVOLVED IN LORCASERIN METABOLISM

Khawja A. Usmani, Weichao G. Chen and Abu J.M. Sadeque
Drug Metabolism and Disposition April 1, 2012, 40 (4) 761-771; DOI: https://doi.org/10.1124/dmd.111.043414

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Research ArticleArticle

HUMAN P450 AND FMO INVOLVED IN LORCASERIN METABOLISM

Khawja A. Usmani, Weichao G. Chen and Abu J.M. Sadeque
Drug Metabolism and Disposition April 1, 2012, 40 (4) 761-771; DOI: https://doi.org/10.1124/dmd.111.043414
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