Inhibition of Terfenadine Metabolism
Inhibition of Terfenadine Metabolism
复制标题
特非那定代谢的抑制
作者：
K. Kivistö;P. Neuvonen;U. Klotz
特非那定是一种非镇静组胺H I受体拮抗剂，在许多国家被广泛使用，无需处方即可获得。特非那定最初被认为具有良好的耐受性，但现在有几份报告表明特非那定的使用与心脏复极化改变之间存在关联。过量、肝功能障碍和同时给予酮康唑（细胞色素P450介导的药物代谢的抑制剂）被确定为特非那定相关心脏毒性的风险因素。[2-5]特非那定是一种前药。经口给药后，其几乎完全首过代谢为2种代谢产物：具有抗组胺特性的活性酸性代谢产物（特非那定羧酸盐）和非活性脱烷基化代谢产物（图1）。[6]因此，在以120 mg/天的常规剂量服用药物的患者中发现可检测的特非那定血浆浓度是不寻常的。然而，特非那定是导致观察到的QT延长的原因。因此，同时给予抑制特非那定代谢的药物可导致特非那定蓄积并诱导潜在致死性室性心律失常，如尖端扭转型室性心动过速。[7]考虑到特非那定和抑制其代谢的药物（如酮康唑、伊曲康唑和红霉素）的广泛使用，可能经常忽略临床显著的相互作用。尽管美国食品药品监督管理局和特非那定生产商做出了努力，但目前对特非那定潜在有害药物相互作用的认识似乎仍不令人满意。最近的数据允许不同的药物，特别是口服抗真菌药和大环内酯类抗生素，干扰特非那定的代谢的潜力进行比较评价。
Terfenadine, a nonsedating histamine H I-receptor antagonist, is widely used and is available without prescription in many countries. Terfenadine was initially considered to have a favourable tolerability profile, but there are now several reports indicating an association between use of terfenadine and altered cardiac repolarisation.l I] Overdose, hepatic dysfunction and coadministration of ketoconazole, an inhibitor of cytochrome P450-mediated drug metabolism, were identified as risk factors for terfenadine-associated cardiotoxicity. [2-5] Terfenadine is a prodrug. After oral administration, it undergoes virtually complete first-pass metabolism to 2 metabolites: an active acid metabolite (terfenadine carboxylate) with antihistaminic properties and an inactive dealkylated metabolite (fig. 1 ).[6] Consequently, it is unusual to find detectable plasma concentrations of terfenadine in patients taking the drug at the usual dosage of 120 mg/day. However, it is terfenadine that is responsible for the observed QT prolongation. Therefore, concurrent administration of drugs that inhibit terfenadine metabolism can result in accumulation of terfenadine and induction of potentially lethal ventricular arrhythmias such as torsade de pointes.[7] Considering the widespread use of terfenadine and drugs inhibiting its metabolism (e.g. ketoconazole, itraconazole and erythromycin), it is likely that clinically significant interactions have often been overlooked. Regardless of the efforts of both the Food and Drug Administration of the US and the manufacturer of terfenadine, it appears that current awareness of the potentially harmful drug interactions with terfenadine remains unsatisfactory. Recent data allow a comparative evaluation of the potential of different drugs, especially oral antifungal agents and macrolide antibiotics, to interfere with the metabolism of terfenadine.
DOI：
10.1152/ajpheart.1998.275.1.h100
发表时间：
1998-07-01
影响因子：
4.8
作者：
Stephenson, AH;Sprague, RS;Lonigro, AJ
通讯作者：
Lonigro, AJ