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Research ArticleArticle

Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics

Lifei Wang, Lisa J. Christopher, Donghui Cui, Wenying Li, Ramaswamy Iyer, W. Griffith Humphreys and Donglu Zhang
Drug Metabolism and Disposition September 2008, 36 (9) 1828-1839; DOI: https://doi.org/10.1124/dmd.107.020255
Lifei Wang
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Lisa J. Christopher
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Donghui Cui
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Wenying Li
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Ramaswamy Iyer
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W. Griffith Humphreys
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Donglu Zhang
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Abstract

N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide (dasatinib, Sprycel, BMS-354825; Bristol-Myers Squibb, Princeton, NJ) is a potent protein kinase inhibitor to treat chronic myeloid leukemia. In vivo studies have shown that the primary oxidative metabolites of dasatinib are M4 (N-dealkylation), M5 (N-oxidation), M6 (carboxylic acid formation), M20, and M24 (hydroxylation). To identify the enzymes responsible for the formation of these metabolites, [14C]-dasatinib and nonradiolabeled dasatinib were incubated with human cDNA-expressed enzymes [cytochromes P450 (P450s) and flavin-containing monooxygenase (FMO) 3] or human liver microsome (HLM) in the presence of selective P450 inhibitors (antibodies and chemical inhibitors). The results of these experiments showed that metabolites M4, M20, and M24 were mainly generated by CYP3A4; M5 was primarily formed by FMO3; and M6 was formed by a cytosolic oxidoreductase. The enzyme kinetic analysis showed that the formation of M4 and M5 in HLM followed the Michaelis-Menten kinetics, and the formation data of M20 and M24 fitted well to a partial substrate inhibition kinetic model. The Km values were determined by the kinetic analysis of the substrate-dependent metabolite formation plots from a large number of incubations with the nonlabeled dasatinib; the Vmax values were calculated with the predetermined Km values and the metabolite formation rates from a limited number of incubations with [14C]dasatinib. The intrinsic formation clearance values (Vmax/Km) of 52, 14, 274, and 20 μl/mg protein/min for the formation of M4, M5, M20, and M24, respectively, suggested that the formation of M20 was more efficient than other metabolites. Collectively, multiple in vitro experiments showed that dasatinib was predominately metabolized by CYP3A4.

Footnotes

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

  • doi:10.1124/dmd.107.020255.

  • ABBREVIATIONS: dasatinib, N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide; ADME, absorption, distribution, metabolism, and excretion; P450, cytochrome P450; DDI, drug-drug interaction; FMO, flavin-containing monooxygenase; HLM, human liver microsome; IS, internal standard; ABT, 1-aminobenzotriazole; TFA, trifluoroacetic acid; HPLC, high-performance liquid chromatography; LC/MS, liquid chromatography/mass spectrometry; MS/MS, tandem mass spectrometry; SRM, selective reaction monitoring; AUC, area under the curve.

  • ↵1 Current affiliation: Department of Drug Metabolism, Merck and Co., Inc., West Point, PA.

    • Received December 19, 2007.
    • Accepted June 9, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (9)
Drug Metabolism and Disposition
Vol. 36, Issue 9
1 Sep 2008
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Research ArticleArticle

Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics

Lifei Wang, Lisa J. Christopher, Donghui Cui, Wenying Li, Ramaswamy Iyer, W. Griffith Humphreys and Donglu Zhang
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1828-1839; DOI: https://doi.org/10.1124/dmd.107.020255

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Research ArticleArticle

Identification of the Human Enzymes Involved in the Oxidative Metabolism of Dasatinib: An Effective Approach for Determining Metabolite Formation Kinetics

Lifei Wang, Lisa J. Christopher, Donghui Cui, Wenying Li, Ramaswamy Iyer, W. Griffith Humphreys and Donglu Zhang
Drug Metabolism and Disposition September 1, 2008, 36 (9) 1828-1839; DOI: https://doi.org/10.1124/dmd.107.020255
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