Evans David C, O'Connor Desmond, Lake Brian G, Evers Raymond, Allen Christopher, Hargreaves Richard
Department of Drug Metabolism, Merck & Co., Inc., 126 East Lincoln Avenue (RY80E-200), Rahway, NJ 07065, USA.
Drug Metab Dispos. 2003 Jul;31(7):861-9. doi: 10.1124/dmd.31.7.861.
"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.
进行了依立曲坦（ETT）的“反应表型分析”研究，以确定其与共同给药药物相互作用的倾向。鉴于已提出此类“曲坦类”药物的核心作用机制，还研究了其作为人P-糖蛋白（P-gp）底物的能力。在使用一组特征明确的人肝微粒体制剂进行的研究中，N-去甲基依立曲坦（DETT）的形成与CYP3A4催化的睾酮6β-羟基化之间具有良好的相关性（r2 = 0.932）。在我们的研究中选择监测DETT，因为它是人体内一种重要的ETT代谢产物，其循环浓度为母体药物的10%至20%。ETT被重组CYP2D6（rCYP2D6）和rCYP3A4代谢为DETT，在较小程度上被rCYP2C9和rCYP2C19代谢。在人肝微粒体中，ETT代谢为DETT的过程被醋竹桃霉素、红霉素、咪康唑和一种针对CYP3A4的抑制性抗体显著抑制，但未被其他主要P450酶的抑制剂抑制。ETT对所研究的任何一种P450酶几乎没有抑制作用。体外研究确定ETT是人类P-gp的良好底物。在跨LLC-MDR1和LLC-Mdr1a细胞单层的双向转运研究中，ETT的BA/AB转运比在9至11之间。这一发现具有体内意义，因为与Mdr1a-/-小鼠相比，Mdr1a+/+小鼠脑中ETT的暴露量降低了40倍。因此，ETT代谢为DETT主要由CYP3A4催化，当与CYP3A4和P-gp活性抑制剂共同给药时，预计血浆浓度会升高。
