Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam
Effect of route of administration of fluconazole on the interaction between fluconazole and midazolam
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DOI：
10.1007/s002280050223
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发表时间：
1997-01-01
影响因子：
2.9
通讯作者：
Neuvonen, PJ
中科院分区：
文献类型：
--
作者：
Ahonen, J;Olkkola, KT;Neuvonen, PJ
目的：咪达唑仑是一种由细胞色素P3A4酶广泛代谢的短效苯二氮卓类催眠药。口服包括氟康唑在内的唑类抗真菌药物，会干扰咪达唑仑在吸收和消除阶段的代谢。我们比较了口服和静脉注射氟康唑对口服咪达唑仑的药代动力学和药效学的影响。方法：9名健康受试者采用双模拟、随机、三期交叉试验。受试者在60min内分别口服氟康唑400 mg和静脉注射生理盐水；口服安慰剂和静脉注射氟康唑400 mg；口服安慰剂和静脉注射生理盐水。口服氟康唑/安慰剂后60min，即相应输液结束时，口服7.5 mg咪达唑仑。结果：与安慰剂相比，口服和静脉注射氟康唑均使咪达唑仑血药浓度-时间曲线下面积(AUC(0-3)，AUC(0-17))增加2~3倍，消除半衰期(Cmax)增加2.5倍，峰值浓度(C-max)增加2~2.5倍。咪达唑仑口服后的AUC(0~3)和C-max显著高于静脉给药后。口服和静脉注射氟康唑均可增强咪达唑仑的药效学作用，但不同时相的药效无差异。结论：口服氟康唑对咪达唑仑代谢的抑制作用强于静脉给药。
Objective: Midazolam is a short-acting benzodiazepine hypnotic extensively metabolized by CYP3A4 enzyme. Orally ingested azole antimycotics, including fluconazole, interfere with the metabolism of oral midazolam during its absorption and elimination phases. We compared the effect of oral and intravenous fluconazole on the pharmacokinetics and pharmacodynamics of orally ingested midazolam.Methods: A double-dummy, randomized, cross-over study in three phases was performed in 9 healthy volunteers. The subjects were given orally fluconazole 400 mg and intravenously saline within 60 min; orally placebo and intravenously fluconazole 400 mg; and orally placebo and intravenously saline. An oral dose of 7.5 mg midazolam was ingested 60 min after oral intake of fluconazole/placebo, i.e. at the end of the corresponding infusion. Plasma concentrations of midazolam, alpha-hydroxymidazolam and fluconazole were determined and pharmacodynamic effects were measured up to 17 h.Results: Both oral and intravenous fluconazole significantly increased the area under the midazolam plasma concentration-time curve (AUC(0-3), AUC(0-17)) 2- to 3-fold, the elimination half-life of midazolam 2.5-fold and its peak concentration (C-max) 2- to 2.5-fold compared with placebo. The AUC(0-3) and the C-max of midazolam were significantly higher after oral than after intravenous administration of fluconazole. Both oral and intravenous fluconazole increased the pharmacodynamic effects of midazolam but no differences were detected between the fluconazole phases.Conclusion: We conclude that the metabolism of orally administered midazolam was more strongly inhibited by oral than by intravenous administration of fluconazole.