Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole
Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole
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DOI：
10.1016/s0009-9236(98)90057-1
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发表时间：
1998-12-01
影响因子：
6.7
通讯作者：
Shader, RI
中科院分区：
文献类型：
--
作者：
Greenblatt, DJ;von Moltke, LL;Shader, RI
背景：唑类抗真菌药可能会损害细胞色素 P450-3A 亚型代谢的药物的肝脏清除率。咪唑并吡啶类催眠药唑吡坦在人体中部分通过 P450-3A 以及许多其他细胞色素代谢。在一项对照临床研究中评估了唑吡坦与 3 种常用唑衍生物的潜在相互作用。方法：在一项随机、双盲、5 路、交叉、临床药代动力学-药效学研究中，12 名志愿者接受了 (A) 唑吡坦安慰剂加唑吡坦 安慰剂，(B) 5 mg 唑吡坦加唑吡坦 安慰剂 (C) 唑吡坦加酮康唑，(D) 唑吡坦加伊曲康唑，(E) 唑吡坦加氟康唑。 结果：与安慰剂一起服用时，唑吡坦的平均表观口服清除率为 422 mL/min，消除半衰期为 1.9 小时。当唑吡坦与酮康唑合用时，清除率显着降低至250 mL/min，半衰期延长至2.4小时。唑吡坦与伊曲康唑或氟康唑合用也降低清除率（320和338 mL/min），但与唑吡坦加安慰剂治疗相比，差异未达到显着性。给药后 4 小时内，唑吡坦诱导的苯二氮卓类激动剂作用（心电图 β 活性增加、数字符号替代测试损伤和延迟回忆）被酮康唑增强，但伊曲康唑或氟康唑则没有增强。结论：唑吡坦与酮康唑合用会损害唑吡坦清除率，并增强其苯二氮卓类激动剂药效学作用。伊曲康唑和氟康唑对唑吡坦动力学和动力学影响较小。这些发现与唑吡坦代谢受到唑类衍生物不同程度损害的体外研究一致。
Background: Azole antifungal agents may impair hepatic clearance of drugs metabolized by cytochrome P450-3A isoforms. The imidazopyridine hypnotic agent zolpidem is metabolized in humans in part by P450-3A, as well as by a number of other cytochromes, Potential interactions of zolpidem with 3 commonly prescribed azole derivatives were evaluated in a controlled clinical study.Methods: In a randomized, double-blind, 5-way, crossover, clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received (A) zolpidem placebo plus azole placebo, (B) 5 mg zolpidem plus azole Placebo (C) zolpidem plus ketoconazole, (D) zolpidem plus itraconazole, and (E) zolpidem plus fluconazole.Results: Mean apparent oral clearance of zolpidem when given with placebo was 422 mL/min, and elimination half-life was 1.9 hours. Clearance was significantly reduced to 250 mL/min when zolpidem was given with ketoconazole, and half-life was prolonged to 2.4 hours, Coadministration of zolpidem with itraconazole or fluconazole also reduced clearance (320 and 338 mL/min), but differences compared to the zolpidem plus placebo treatment did not reach significance. Zolpidem-induced benzodiazepine agonist effects (increased electrocardiographic beta activity, digit-symbol substitution test impairment, and delayed recall) during the first 4 hours after dosage were enhanced by ketoconazole but not by itraconazole or fluconazole,Conclusion: Coadministration of zolpidem with ketoconazole impairs zolpidem clearance and enhances its benzodiazepine-like agonist pharmacodynamic effects. Itraconazole and fluconazole had a small influence on zolpidem kinetics and dynamics. The findings are consistent with in vitro studies of differentially impaired zolpidem metabolism by azole derivatives.