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In vitro prediction and in vivo verification of enantioselective human tofisopam metabolite profiles

Academic Article
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Overview

authors

  • Cameron, Michael
  • Wright, J.
  • Black, C. B.
  • Ye, N.

publication date

  • October 2007

journal

  • Drug Metabolism and Disposition  Journal

abstract

  • In vitro studies were conducted to elucidate the metabolic profiles of and the enzymes responsible for the metabolism of (R)- and (S)-tofisopam (1-(3,4-dimethoxyphenyl)-5-ethyl-7,8-dimethoxy-4-methyl-5H-2,3-benzodiazepine). Large differences were observed between the two enantiomers. The major metabolite in incubations of 500 ng/ml (approximately 1.3 microM) (R)-tofisopam in human liver microsomes corresponded to demethylation of the methoxy group at the 4-position of the phenyl ring (M3). Incubating (R)-tofisopam with recombinant cytochrome P450 (P450) or with human liver microsomes and isoform-selective P450 chemical inhibitors indicated that M3 was primarily catalyzed by CYP2C9. Similar incubations with S-tofisopam indicated that the primary metabolite was due to demethylation of the methoxy group at the 7-position of the benzodiazepine ring (M1), and this reaction was catalyzed primarily by CYP3A4. The primary metabolites of both enantiomers were further demethylated to form a common didemethylated metabolite (M5) where the methoxy groups at positions 4 and 7 are demethylated. Analysis of plasma and urine samples from human clinical trials confirmed the in vitro observations. Subjects orally treated with 200 mg b.i.d. (R)-tofisopam had a 2-h M1/M3 plasma ratio of 1:29 and a ratio of 1:123 in urine, whereas patients orally administered (S)-tofisopam at 150 mg/kg t.i.d. had opposite M1 to M3 ratios of 8:1 in plasma and 6:1 in urine.

subject areas

  • Adult
  • Benzodiazepines
  • Cytochrome P-450 Enzyme System
  • Female
  • Humans
  • Male
  • Microsomes, Liver
  • Middle Aged
  • Recombinant Proteins
  • Stereoisomerism
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Identity

International Standard Serial Number (ISSN)

  • 0090-9556

Digital Object Identifier (DOI)

  • 10.1124/dmd.107.015875

PubMed ID

  • 17646282
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Additional Document Info

start page

  • 1894

end page

  • 1902

volume

  • 35

issue

  • 10

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