Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs
Effect of multiple dosing of ketoconazole on pharmacokinetics of midazolam, a cytochrome P-450 3A substrate in beagle dogs
复制标题
DOI：
10.1124/dmd.30.1.63
复制
发表时间：
2002-01-01
影响因子：
3.9
通讯作者：
Kokue, E
中科院分区：
文献类型：
--
作者：
Kuroha, M;Azumano, A;Kokue, E
为评价多次给药酮康唑(KTZ)对肝脏细胞色素P3A(CyP3A)的影响，研究了咪达唑仑(MDZ)0.5 mg/kg静注给药前和给药过程中的药代动力学。犬(n=4)口服KTZ片，每日200 mg，连续30天。联合应用KTZ后，MDZ的t(1/2β)在第1天(2倍)和第30天(3倍)均显著增加。MDZ的整体清除率(CLtot)在KTZ治疗开始后的前5天逐渐下降，此后CLtot似乎达到平台期(四分之一)，这取决于KTZ的血药浓度。用狗肝微粒体(n=5)研究了KTZ对MDZ生物转化的影响。KTZ对MDZ1‘-羟化和4-羟化的K-I分别为0.0237和0.111微米，表明KTZ对犬肝脏细胞色素P3A活性有广泛的抑制作用。由KTZ的体外K-I值和血浆中药物的游离浓度估算的CLtot值与MDZ的体内CLtot值一致。本研究结果提示，在体内评价多次给药对肝脏细胞色素P3A的影响时，有必要进行KTZ治疗，直至血药浓度达到稳态。此外，通过KTZ的游离分数和血浆中药物的游离浓度校正的K-I值可以实现精确的体内外调节。
To evaluate effects of multiple dosing of ketoconazole (KTZ) on hepatic CYP3A, the pharmacokinetics of intravenous midazolam (MDZ, 0.5 mg/kg) before and during multiple dosing of KTZ were investigated in beagle dogs. KTZ tablets were given orally to dogs (n = 4) for 30 days (200 mg b.i.d.). With coadministration of KTZ, t(1/2 beta) of MDZ were significantly increased both on day 1 (2-fold) and on day 30 (3-fold). Total body clearance (CLtot) of MDZ declined gradually during the first 5 days after the start of KTZ treatment, and thereafter CLtot appeared to reach a plateau phase (one-fourth), depending on plasma KTZ concentrations. The effects of KTZ on the biotransformation of MDZ were also investigated using dog liver microsomes (n = 5). The K-i values of KTZ for MDZ 1'-hydroxylation and 4-hydroxylation were 0.0237 and 0.111 muM, respectively, indicating that KTZ extensively inhibits hepatic CYP3A activity in dogs. CLtot values estimated from in vitro K-i values corrected by unbound traction of KTZ and unbound concentrations of the drug in plasma were consistent with in vivo CLtot of MDZ. The results in this study suggest that KTZ treatment is necessary until plasma concentrations of the drug reach a steady state to evaluate the effect of multiple dosing of the drug on hepatic CYP3A in vivo. In addition, it is suggested that K-i values corrected by unbound fraction of KTZ and unbound concentrations of the drug in plasma enable precise in vitro-in vivo scaling.