Human hepatocytes in primary culture predict lack of cytochrome P-450 3A4 induction by eletriptan in vivo

Eletriptan (Relpax) is a novel 5-hydroxytryptamine (serotonin)(1D/1B) agoni st 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 det ectable at eletriptan concentrations of 5 mu M and lower. The amplitude of the increase in CYP3A4 protein and activity by 25 mu M eletriptan was signi ficantly lower, with a mean of 19 (P = .0015) and 26% (P = .0002), respecti vely, of that observed in response to 25 mM rifampicin. CYP2A6, a protein w ith minor pharmacological implication, also was induced by eletriptan and r ifampicin 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 o f eletriptan in humans after a therapeutic dose (maximum 80 mg) is 0.5 mu M , the in vitro model would predict no clinically significant induction of C YP3A4 protein in vivo. This has been confirmed subsequently in a clinical s tudy, with 6 beta-hydroxycortisol/cortisol ratios as marker of CYP3A4 activ ity. Eletriptan is therefore not an inducer of CYP3A4 at clinical doses.