title: Human hepatocytes in primary culture predict lack of cytochrome P-450 3A4 induction by eletriptan in vivo.
abstract: Eletriptan (Relpax) is a novel 5-hydroxytryptamine (serotonin)(1D/1B) agonist currently in development for the acute treatment of migraine. The aim of this work was to evaluate the relative induction potency of eletriptan in vitro compared with well characterized cytochrome P-450 (CYP) inducers with primary cultures of human hepatocytes and to relate this to the situation in vivo. Eletriptan was a weak inducer of CYP3A4 protein and cyclosporin A oxidation in four of the six cultures used, whereas rifampicin was a potent inducer in all cultures. Induction was concentration dependent and not detectable at eletriptan concentrations of 5 microM and lower. The amplitude of the increase in CYP3A4 protein and activity by 25 microM eletriptan was significantly lower, with a mean of 19 (P =.0015) and 26% (P =.0002), respectively, of that observed in response to 25 microM rifampicin. CYP2A6, a protein with minor pharmacological implication, also was induced by eletriptan and rifampicin in two cultures but was not detected in the others. The levels of other CYP proteins, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, were not affected by eletriptan. Because the maximum blood concentration of eletriptan in humans after a therapeutic dose (maximum 80 mg) is 0.5 microM, the in vitro model would predict no clinically significant induction of CYP3A4 protein in vivo. This has been confirmed subsequently in a clinical study, with 6beta-hydroxycortisol/cortisol ratios as marker of CYP3A4 activity. Eletriptan is therefore not an inducer of CYP3A4 at clinical doses.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Montpellier, France.
authors.forename: L
authors.initials: L
authors.lastname: Pichard-Garcia
authors.forename: R
authors.initials: R
authors.lastname: Hyland
authors.forename: J
authors.initials: J
authors.lastname: Baulieu
authors.forename: J M
authors.initials: JM
authors.lastname: Fabre
authors.forename: A
authors.initials: A
authors.lastname: Milton
authors.forename: P
authors.initials: P
authors.lastname: Maurel
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000187:drug effects*; D053938:DNA Fragmentation; D017931:DNA Primers; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000187:drug effects*; D011759:Pyrrolidines / Q000494:pharmacology* / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D014363:Tryptamines
chemical_list: D017931:DNA Primers; D007211:Indoles; D011759:Pyrrolidines; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C115647:eletriptan; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D006854:Hydrocortisone