酮康唑对健康受试者体内丙咪嗪和地昔帕明药代动力学的影响。
Effect of ketoconazole on the pharmacokinetics of imipramine and desipramine in healthy subjects.
作者信息
Spina E, Avenoso A, Campo G M, Scordo M G, Caputi A P, Perucca E
机构信息
Institute of Pharmacology, University of Messina, Italy.
出版信息
Br J Clin Pharmacol. 1997 Mar;43(3):315-8. doi: 10.1046/j.1365-2125.1997.00539.x.
AIMS
The aim of the study was to characterize further the role of CYP3A4 in the metabolism of tricyclic antidepressants.
METHODS
The effect of oral ketoconazole (200 mg day-1 for 14 days) on the kinetics of a single oral dose of imipramine (100 mg) and desipramine (100 mg) was evaluated in two groups of six healthy male subjects.
RESULTS
Ketoconazole administration was associated with a decrease in imipramine apparent oral clearance (from 1.16 +/- 0.21 to 0.96 +/- 0.20 l h-1 kg-1, mean +/- s.d.; P < 0.02), a prolongation in imipramine half-life (from 16.7 +/- 3.3 to 19.2 +/- 5.4 h, P < 0.05) and a decrease in area under the curve of metabolically derived desipramine (from 3507 +/- 1707 to 3180 +/- 1505 nmol l-1 h, P < 0.05), whereas concentrations of 2-hydroxy-imipramine were unaffected. In the subjects given desipramine, no significant changes in desipramine and 2-hydroxy-desipramine kinetics were observed during ketoconazole treatment.
CONCLUSIONS
These findings indicate that ketoconazole, a relatively specific inhibitor of CYP3A4, inhibits the N-demethylation of imipramine without affecting the 2-hydroxylation of imipramine and desipramine. This interaction, confirms that CYP3A4 plays a role in the demethylation of tricyclic antidepressants.
目的
本研究旨在进一步明确细胞色素P450 3A4（CYP3A4）在三环类抗抑郁药代谢中的作用。
方法
在两组各6名健康男性受试者中，评估口服酮康唑（每日200 mg，共14天）对单次口服剂量丙咪嗪（100 mg）和地昔帕明（100 mg）动力学的影响。
结果
服用酮康唑后，丙咪嗪的表观口服清除率降低（从1.16±0.21降至0.96±0.20 l·h⁻¹·kg⁻¹，均值±标准差；P<0.02），丙咪嗪半衰期延长（从16.7±3.3小时延长至19.2±5.4小时，P<0.05），代谢生成的地昔帕明曲线下面积减小（从3507±1707降至3180±1505 nmol·l⁻¹·h，P<0.05），而2-羟基丙咪嗪的浓度未受影响。给予地昔帕明的受试者在酮康唑治疗期间，地昔帕明和2-羟基地昔帕明的动力学未观察到显著变化。
结论
这些发现表明，酮康唑作为一种相对特异性的CYP3A4抑制剂，抑制丙咪嗪的N-去甲基化，而不影响丙咪嗪和地昔帕明的2-羟基化。这种相互作用证实了CYP3A4在三环类抗抑郁药去甲基化中发挥作用。
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