title: Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein.
abstract: "Reaction phenotyping" studies were performed with eletriptan (ETT) to determine its propensity to interact with coadministered medications. Its ability to serve as a substrate for human P-glycoprotein (P-gp) was also investigated since a central mechanism of action has been proposed for this "triptan" class of drug. In studies with a characterized bank of human liver microsome preparations, a good correlation (r2 = 0.932) was obtained between formation of N-desmethyl eletriptan (DETT) and CYP3A4-catalyzed testosterone 6 beta-hydroxylation. DETT was selected to be monitored in our studies since it represents a significant ETT metabolite in humans, circulating at concentrations 10 to 20% of those observed for parent drug. ETT was metabolized to DETT by recombinant CYP2D6 (rCYP2D6) and rCYP3A4, and to a lesser extent by rCYP2C9 and rCYP2C19. The metabolism of ETT to DETT in human liver microsomes was markedly inhibited by troleandomycin, erythromycin, miconazole, and an inhibitory antibody to CYP3A4, but not by inhibitors of other major P450 enzymes. ETT had little inhibitory effect on any of the P450 enzymes investigated. ETT was determined to be a good substrate for human P-gp in vitro. In bidirectional transport studies across LLC-MDR1 and LLC-Mdr1a cell monolayers, ETT had a BA/AB transport ratio in the range 9 to 11. This finding had significance in vivo since brain exposure to ETT was reduced 40-fold in Mdr1a+/+ relative to Mdr1a-/- mice. ETT metabolism to DETT is therefore catalyzed primarily by CYP3A4, and plasma concentrations are expected to be increased when coadministered with inhibitors of CYP3A4 and P-gp activity.
authors.affiliation: Department of Drug Metabolism, Merck & Co., Inc., 126 East Lincoln Avenue (RY80E-200), Rahway, NJ 07065, USA. david_c_evans@merck.com
authors.forename: David C
authors.initials: DC
authors.lastname: Evans
authors.forename: Desmond
authors.initials: D
authors.lastname: O'Connor
authors.forename: Brian G
authors.initials: BG
authors.lastname: Lake
authors.forename: Raymond
authors.initials: R
authors.lastname: Evers
authors.forename: Christopher
authors.initials: C
authors.lastname: Allen
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004917:Erythromycin; D019450:Genes, MDR / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008825:Miconazole; D008862:Microsomes, Liver / Q000201:enzymology; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D013223:Statistics as Topic; D018170:Sumatriptan / Q000008:administration & dosage / Q000493:pharmacokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D014217:Troleandomycin; D014363:Tryptamines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065607:Cytochrome P-450 Enzyme Inhibitors; D007211:Indoles; D023303:Oxazolidinones; D010880:Piperidines; D011759:Pyrrolidines; D011994:Recombinant Proteins; D014230:Triazoles; D014363:Tryptamines; C115647:eletriptan; C089750:zolmitriptan; C093622:rizatriptan; D004917:Erythromycin; C482239:N-desmethyl eletriptan; D008825:Miconazole; D018170:Sumatriptan; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D001189:Aryl Hydrocarbon Hydroxylases; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C100638:cytochrome P-450 CYP3A6 (rabbit); D010089:Oxidoreductases, N-Demethylating; C106783:naratriptan