Ito Kiyomi, Ogihara Kanako, Kanamitsu Shin-Ichi, Itoh Tomoo
School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Drug Metab Dispos. 2003 Jul;31(7):945-54. doi: 10.1124/dmd.31.7.945.
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 kinact) involved in midazolam alpha-hydroxylation were 12.6 microM and 0.0240 min-1, respectively, for erythromycin, 41.4 microM and 0.0423 min-1, respectively, for clarithromycin, and 623 microM 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.
临床研究表明，口服咪达唑仑后，同时服用红霉素和克拉霉素会使咪达唑仑的血浆浓度大幅升高，而阿奇霉素对咪达唑仑浓度影响较小。已知几种大环内酯类抗生素是基于机制的CYP3A抑制剂，CYP3A是一种负责咪达唑仑羟基化的细胞色素P450同工酶。本研究的目的是基于体外研究定量预测人类体内涉及不同抑制效力的大环内酯类抗生素的药物相互作用。将人肝微粒体对咪达唑仑的α-羟基化和4-羟基化作为CYP3A介导的代谢反应进行评估，并检测与大环内酯类药物预孵育的效果。在NADPH存在下，与大环内酯类药物预孵育后，咪达唑仑的羟基化以时间和浓度依赖性方式受到抑制，而未预孵育时几乎未观察到抑制作用。参与咪达唑仑α-羟基化的酶失活动力学参数（K'app和kinact），红霉素分别为12.6μM和0.0240 min-1，克拉霉素分别为41.4μM和0.0423 min-1，阿奇霉素分别为623μM和0.0158 min-1。4-羟基化途径也得到了类似结果。然后，这些参数以及报道的咪达唑仑和大环内酯类药物的药代动力学参数被用于基于生理血流模型模拟体内相互作用。口服咪达唑仑后，预测在分别用红霉素（500 mg每日三次，共5天或6天）预处理后，其浓度-时间曲线下面积（AUC）将增加2.9倍或3.0倍，在用克拉霉素（分别为250 mg每日两次，共5天或500 mg每日两次，共7天）预处理后将增加2.1倍或2.5倍，而阿奇霉素（500 mg每日一次，共3天）预计对咪达唑仑AUC影响较小。这些结果与报道的体内观察结果非常吻合。
