Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes
Prediction of the in vivo interaction between midazolam and macrolides based on in vitro studies using human liver microsomes
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DOI：
10.1124/dmd.31.7.945
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发表时间：
2003-07-01
影响因子：
3.9
通讯作者：
Itoh, T
中科院分区：
文献类型：
--
作者：
Ito, K;Ogihara, K;Itoh, T
临床研究表明，红霉素和克拉霉素联合给药后咪达唑仑的血药浓度大大增加，而阿奇霉素对咪达唑仑浓度的影响很小。已知几种大环内酯类抗生素是CYP 3A的基于机制的抑制剂，CYP 3A是一种负责咪达唑仑羟基化的细胞色素P450亚型。本研究的目的是根据体外研究定量预测具有不同抑制效力的大环内酯类抗生素在人体内的体内药物相互作用。将人肝微粒体对咪达唑仑的α-和4-羟基化作用评价为CYP 3A介导的代谢反应，并检查了与大环内酯类药物预孵育的影响。在NADPH存在下，与大环内酯类预孵育后，咪达唑仑的羟基化以时间和浓度依赖性方式受到抑制，而在未预孵育的情况下几乎没有观察到抑制作用。咪达唑仑α-羟基化中酶失活的动力学参数（K '（app）和k（inact）），红霉素分别为12.6 μ M和0.0240 min（-1），克拉霉素分别为41.4 μ M和0.0423 min（-1），阿奇霉素分别为623 μ M和0.0158 min（-1）。对于4-羟基化途径获得了类似的结果。这些参数和报告的咪达唑仑和大环内酯类药物的药代动力学参数，然后用于模拟在生理流动模型的基础上在体内的相互作用。口服给药后咪达唑仑的浓度-时间曲线下面积（AUC）预计在红霉素（500 mg t.i.d.分别为5或6天）和克拉霉素（250 mg b.i.d.）的2.1或2.5倍。5天或500 mg b.i.d. 7天），而阿奇霉素（500 mg o.d. 3天）对咪达唑仑AUC的影响很小。这些结果与报告的体内观察结果一致。
Clinical studies have revealed that plasma concentrations of midazolam after oral administration are greatly increased by coadministration of erythromycin and clarithromycin, whereas azithromycin has little effect on midazolam concentrations. Several macrolide antibiotics are known to be mechanism-based inhibitors of CYP3A, a cytochrome P450 isoform responsible for midazolam hydroxylation. The aim of the present study was to quantitatively predict in vivo drug interactions in humans involving macrolide antibiotics with different inhibitory potencies based on in vitro studies. alpha- and 4-Hydroxylation of midazolam by human liver microsomes were evaluated as CYP3A-mediated metabolic reactions, and the effect of preincubation with macrolides was examined. The hydroxylation of midazolam was inhibited in a time- and concentration-dependent manner following preincubation with macrolides in the presence of NADPH, whereas almost no inhibition was observed without preincubation. The kinetic parameters for enzyme inactivation (K'(app) and k(inact)) involved in midazolam alpha-hydroxylation were 12.6 muM and 0.0240 min(-1), respectively, for erythromycin, 41.4 muM and 0.0423 min(-1), respectively, for clarithromycin, and 623 muM and 0.0158 min(-1), respectively, for azithromycin. Similar results were obtained for the 4-hydroxylation pathway. These parameters and the reported pharmacokinetic parameters of midazolam and macrolides were then used to simulate in vivo interactions based on a physiological flow model. The area under the concentration-time curve (AUC) of midazolam after oral administration was predicted to increase 2.9- or 3.0-fold following pretreatment with erythromycin (500 mg t.i.d. for 5 or 6 days, respectively) and 2.1- or 2.5-fold by clarithromycin (250 mg b.i.d. for 5 days or 500 mg b.i.d. for 7 days, respectively), whereas azithromycin (500 mg o.d. for 3 days) was predicted to have little effect on midazolam AUC. These results agreed well with the reported in vivo observations.