Identification of the human liver enzymes involved in the metabolism of the antimigraine agent almotriptan.
Almotriptan is a novel highly selective 5-hydroxytryptamine(1B/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 gamma-aminobutyric acid metabolite. Almotriptan is also metabolized at the dimethylaminoethyl group by N-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 gamma-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.
Salva
Miquel
M
Department of Pharmacokinetics and Drug Metabolism, Almirall Prodesfarma SA, Research Centre, Laurea Miro 408-410, E-08980 Sant Feliu de Llobregat, Barcelona, Spain. msalva@almirallprodesfarma.com
Jansat
Josep M
JM
Martinez-Tobed
Antonio
A
Palacios
Jose M
JM
D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000201:enzymology*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008928:Mitochondria / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013997:Time Factors; D014363:Tryptamines
D002247:Carbon Isotopes; D004791:Enzyme Inhibitors; D007211:Indoles; D020033:Protein Isoforms; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C409045:almotriptan; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases