Vol. 28, Issue 1, 51-57, January 2000

Human Hepatocytes in Primary Culture Predict Lack of Cytochrome P-450 3A4 Induction by Eletriptan In Vivo

Lydiane Pichard-Garcia, Ruth Hyland, Jean Baulieu, Jean-Michel Fabre, Ashley Milton, and Patrick Maurel

Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Montpellier, France (L.P.-G., J.-M.F., P.M.); Department of Drug Metabolism, Pfizer Central Research, Sandwich, Kent, United Kingdom (R.H.); Chirurgie Digestive, Hopital de la Croix Rousse, Lyon, France (J.B.); Service de Chirurgie, Institut des Maladies de l'Appareil Digestif, Hopital Saint Eloi, Montpellier, France (J.-M.F.); and Early Clinical Research Group, Pfizer Central Research, Sandwich, Kent, United Kingdom (A.M.)

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 µM and lower. The amplitude of the increase in CYP3A4 protein and activity by 25 µM eletriptan was significantly lower, with a mean of 19 (P = .0015) and 26% (P = .0002), respectively, of that observed in response to 25 µM 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 µM, 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 6-hydroxycortisol/cortisol ratios as marker of CYP3A4 activity. Eletriptan is therefore not an inducer of CYP3A4 at clinical doses.