Studies on the Metabolic Fate of M17055, a Novel Diuretic (4) : Species Difference in Metabolic Pathway and Identification of Human CYP Isoform Responsible for the Metabolism of M17055

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Author(s)

    • NAKAJIMA Hiroyuki
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • NAKANISHI Takeshi
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • NAKAI Kiyohiko
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • MATSUMOTO Shigeki
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • IDA Keiichi
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • OGIHARA Takuo
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd
    • OHZAWA Nobuo
    • Drug Metabolism and Pharmacokinetics Laboratory, Research Center, Mochida Pharmaceutical Co., Ltd

Abstract

  The metabolic profile of M17055, a novel diuretic, after administration to experimental animals and after incubation with human liver microsomes was investigated.<br> 1. Extensive metabolism was observed in rats and monkeys and the structures of six metabolites (RU1, RU2, and RU3 from rat urine or liver perfusate; MU1, MU2 and MU3 from monkey urine) were assumed or identified. The clear species difference of metabolism was revealed between rats and a monkey with different structures of the isolated metabolites.<br> 2. When these metabolites were quantified using radioactive material, RU3, RU1 and MU3 were considered to be major metabolites in rat urine, rat bile and monkey urine respectively, while in a dog, unchanged drug was observed as the major component indicating only little metabolism occurred in dog, when administered intravenously.<br> 3. RU1 and RU2 were also generated from [<sup>14</sup>C]M17055 after incubation with human liver microsomes, suggesting that the metabolic pathway of M17055 in humans involves that observed in rats.<br> 4. [<sup>14</sup>C]M17055 metabolism in human liver microsomes was inhibited by CYP2C8/9 and CYP3A4/5 inhibitors, and also by the antibodies that recognize CYP2C8/9/19 and CYP3A4. Significant correlations were observed between the rate of [<sup>14</sup>C]M17055 metabolism and the activity of testosterone 6β-hydroxylation or tolbutamide methyl-hydroxylation. cDNA-expressed CYP3A4 and CYP2C9 could catalyze the metabolism of [<sup>14</sup>C]M17055. These results suggest that the metabolism of M17055 in human liver microsomes is catalyzed mainly by CYP3A4 and CYP2C9.<br>

Journal

  • Drug Metabolism and Pharmacokinetics

    Drug Metabolism and Pharmacokinetics 17(1), 60-74, 2002-03-29

    The Japanese Society for the Study of Xenobiotics

References:  29

Cited by:  1

Codes

  • NII Article ID (NAID)
    10008198116
  • NII NACSIS-CAT ID (NCID)
    AA1162652X
  • Text Lang
    ENG
  • Article Type
    Journal Article
  • ISSN
    09161139
  • Data Source
    CJP  CJPref  J-STAGE 
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