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

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT: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.

A Comprehensive Assessment of Repaglinide Metabolic Pathways: Impact of Choice of In Vitro System and Relative Enzyme Contribution to In Vitro Clearance

“…Aldehyde oxidase is one of the cytosolic enzymes recognized to be of increasing relevance with newly developed drugs (Zientek et al, 2010;Hutzler et al, 2012), in particular for heterocycle-containing compounds (Garattini et al, 2008;Pryde et al, 2010). In contrast, aldehyde dehydrogenase, another cytosolic enzyme, has shown high affinity toward aliphatic aldehydes (Panoutsopoulos et al, 2004) and has been often involved in tandem with initial P450 oxidation (Salva et al, 2003;Ekhart et al, 2008). Aldehyde oxidase and aldehyde dehydrogenase were both investigated in the current study as potential enzymes involved in the formation of repaglinide M2 metabolite.…”

“…The rationale for inhibitor selection and corresponding concentrations was to ensure inhibition of one metabolic pathway of repaglinide at the time. The selected inhibitors were gemfibrozil glucuronide (75 M) (Ogilvie et al, 2006), ketoconazole (0.2 M, selected concentration is expected to have minimal inhibitory effect on CYP2C8) (Ong et al, 2000;Shitara et al, 2003), disulfiram (10 M) (Hu et al, 1997;Salva et al, 2003), and raloxifene (0.05 M) (Obach et al, 2004). Raloxifene has also been shown to be a time-dependent inhibitor of CYP3A4, resulting in K I estimates approximating 10 M (Chen et al, 2002).…”

Drug disposition of chiral and achiral drug substrates metabolized by cytochrome P450 2D6 isozyme: case studies, analytical perspectives and developmental implications

“…Since the enantiomers of fluoxetine are both substrates for CYP2D6 pathway and also a potent inhibitor of CYP2D6 isozyme, Fjordside et al (1999) investigated the stereoselective metabolism of fluoxetine in PMs Salva et al, 2003;McEnroe and Fleishaker, 2005Horikiri et al, 1998a,b Mautz et al, 1995Narimatsu et al, 2002Fujimaki, 1991, 1994Ducharame and Farinotti, 1996;Projean et al, 2003Yasuda et al, 2002Nomura et al, 1997Muralidharan et al, 1996Yeung et al, 1993;Hubbard et al, 1993;Chaudhary et al, 1988;Turano et al, 1972;Hollister and Curry, 1971;Sved et al, 1971;Jaworski et al, 1990Niwa et al, 2000Loh et al, 1986 Olesen andLinnet, 1999;Rochat et al, 1...…”

Reaction Phenotyping

“…Purifi ed recombinant human MAO -A and MAO -B are now available (Edmondson et al, 2004 ). Relatively selective inhibitors have also been reported (Fowler et al, 1981 ); parglycine is a broad MAO inhibitor, clorgyline is a selective irreversible inhibitor of MAO -A, and l -deprenyl and selegiline are selective irreversible inhibitors of MAO -B. Identifi cation of MAO involved in oxidative deamination reactions can, therefore, be readily assessed using these tools (Kalgutkar et al, 2001 ;Salva et al, 2003 ;Erickson et al, 2007 ).…”