Jurima-Romet M, Huang H S, Beck D J, Li A P
Bureau of Drug Research, Drugs Directorate, Health Protection Branch, Health Canada, Banting Research Centre 2201C, Tunney's Pasture, Ottawa K1A 0L2, Canada.
Toxicol In Vitro. 1996 Dec;10(6):655-63. doi: 10.1016/s0887-2333(96)00056-2.
Terfenadine has been associated with several adverse drug interactions and it was of interest to develop in vitro systems to explain and predict such interactions. The metabolism of terfenadine was studied using intact hepatocytes from primary human and rat hepatocyte cultures, and the immortalized human hepatoma cell line HepG2. Rates and routes of biotransformation were analysed by HPLC. Terfenadine was extensively metabolized by all three cell culture systems during exposure periods ranging from 4 to 24 hr. Human and rat hepatocytes and HepG2 cells formed products of C-oxidation (an acid metabolite and its precursor alcohol metabolite). Human hepatocytes also formed the N-dealkylation product azacyclonol. Several cytochrome P4503A (CYP3A) substrates and inhibitors were evaluated for their ability to inhibit terfenadine biotransformation. In rat hepatocytes, ketoconazole, erythromycin and troleandomycin failed to inhibit; in HepG2 cells, only ketoconazole potently inhibited terfenadine metabolism. In human hepatocytes, ketoconazole, itraconazole, erythromycin, troleandomycin, cyclosporin and naringenin inhibited terfenadine metabolism. The results suggest that human hepatocytes may be a useful system for screening for inhibitors of terfenadine metabolism.
特非那定与多种不良药物相互作用有关，因此开发体外系统来解释和预测此类相互作用很有意义。使用原代人肝细胞和大鼠肝细胞培养物中的完整肝细胞以及永生化人肝癌细胞系HepG2研究了特非那定的代谢。通过高效液相色谱法分析生物转化的速率和途径。在4至24小时的暴露期间，所有三种细胞培养系统均使特非那定发生广泛代谢。人肝细胞、大鼠肝细胞和HepG2细胞形成了C-氧化产物（一种酸性代谢物及其前体醇代谢物）。人肝细胞还形成了N-脱烷基产物氮杂环醇。评估了几种细胞色素P4503A（CYP3A）底物和抑制剂抑制特非那定生物转化的能力。在大鼠肝细胞中，酮康唑、红霉素和醋竹桃霉素未能产生抑制作用；在HepG2细胞中，只有酮康唑能有效抑制特非那定的代谢。在人肝细胞中，酮康唑、伊曲康唑、红霉素、醋竹桃霉素、环孢素和柚皮素抑制了特非那定的代谢。结果表明，人肝细胞可能是筛选特非那定代谢抑制剂的有用系统。
