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Research ArticleArticle

Identification of the Human Liver Enzymes Involved in the Metabolism of the Antimigraine Agent Almotriptan

Miquel Salva, Josep M. Jansat, Antonio Martinez-Tobed and Jose M. Palacios
Drug Metabolism and Disposition April 2003, 31 (4) 404-411; DOI: https://doi.org/10.1124/dmd.31.4.404
Miquel Salva
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Josep M. Jansat
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Antonio Martinez-Tobed
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Jose M. Palacios
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Abstract

Almotriptan is a novel highly selective 5-hydroxytryptamine1B/1D agonist developed for the acute oral treatment of migraine. The in vitro metabolism of almotriptan has been investigated using human liver subcellular fractions and cDNA-expressed human enzymes, to study the metabolic pathways and identify the enzymes responsible for the formation of the major metabolites. Specific enzymes were identified by correlation analysis, chemical inhibition studies, and incubation with various cDNA expressed human enzymes. Human liver microsomes and S9 fraction metabolize almotriptan by 2-hydroxylation of the pyrrolidine group to form a carbinolamine metabolite intermediate, a reaction catalyzed by CYP3A4 and CYP2D6. This metabolite is further oxidized by aldehyde dehydrogenase to the open ring γ-aminobutyric acid metabolite. Almotriptan is also metabolized at the dimethylaminoethyl group byN-demethylation, a reaction that is carried out by five different cytochrome P450s, flavin monooxygenase-3 mediated N-oxidation, and MAO-A catalyzed oxidative deamination to form the indole acetic acid and the indole ethyl alcohol derivatives of almotriptan. The use of human liver mitochondria confirmed the contribution of MAO-A to the metabolism of almotriptan. Both, the γ-aminobutyric acid and the indole acetic acid metabolites have been found to be the major in vivo metabolites of almotriptan in humans. In addition, different clinical trials conducted to study the effects of CYP3A4, CYP2D6, and MAO-A on the pharmacokinetics of almotriptan confirmed the involvement of these enzymes in the metabolic clearance of this drug and that no dose changes are required in the presence of inhibitors of these enzymes.

Footnotes

  • Abbreviations used are::
    Almotriptan
    3-(2-dimethylaminoethyl)-5-(1-pyrrodinylsulfonylmethyl)-1H-indole
    5HT
    5-hydroxytryptamine
    P450
    cytochrome P450
    MAO
    monoamine oxidase
    LAS-31936
    3-[1-methyl-4-piperidinyl]-N-methyl-1H-indole-3-ethanesulfonamide
    PMSF
    phenylmethylsulfonyl fluoride
    disulfiram
    tetraethylthiuram disulfide
    DDTC
    diethyldithiocarbamate
    HPLC
    high performance liquid chromatography
    FMO
    flavin monooxygenase
    AO
    aldehyde oxidase
    XO
    xanthine oxidase
    • Received September 5, 2002.
    • Accepted December 18, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 31 (4)
Drug Metabolism and Disposition
Vol. 31, Issue 4
1 Apr 2003
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Research ArticleArticle

Identification of the Human Liver Enzymes Involved in the Metabolism of the Antimigraine Agent Almotriptan

Miquel Salva, Josep M. Jansat, Antonio Martinez-Tobed and Jose M. Palacios
Drug Metabolism and Disposition April 1, 2003, 31 (4) 404-411; DOI: https://doi.org/10.1124/dmd.31.4.404

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Research ArticleArticle

Identification of the Human Liver Enzymes Involved in the Metabolism of the Antimigraine Agent Almotriptan

Miquel Salva, Josep M. Jansat, Antonio Martinez-Tobed and Jose M. Palacios
Drug Metabolism and Disposition April 1, 2003, 31 (4) 404-411; DOI: https://doi.org/10.1124/dmd.31.4.404
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