Physiologically Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin
Physiologically Based Pharmacokinetic Model of Mechanism-Based Inhibition of CYP3A by Clarithromycin
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DOI：
10.1124/dmd.109.028746
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发表时间：
2010-02-01
影响因子：
3.9
通讯作者：
Hall, Stephen D.
中科院分区：
文献类型：
--
作者：
Quinney, Sara K.;Zhang, Xin;Hall, Stephen D.
当CYP 3A抑制剂本身被CYP 3A代谢时，由于CYP 3A机制抑制剂导致的临床药物相互作用（DDI）的预测是复杂的，如克拉霉素。先前试图预测克拉霉素对CYP 3A底物的影响，例如。例如，在一个实施例中，咪达唑仑不能解释克拉霉素的非线性代谢。开发了克拉霉素和咪达唑仑代谢的半生理学药代动力学模型，纳入了CYP 3A和非CYP 3A机制的肝脏和肠道代谢。在两个研究中心均发生了克拉霉素导致的CYP 3A失活。从体外来源获得的克拉霉素的K-I和k（无效）值无法准确预测克拉霉素对CYP 3A活性的临床影响。一种迭代方法确定了预测克拉霉素对咪达唑仑体内作用的最佳值，在肝脏和肠道中，K-i为5.3 μ M，k（无效）分别为0.4和4 h（-1）。结合克拉霉素的CYP 3A依赖性代谢，能够预测其非线性药代动力学。500 mg克拉霉素每日两次口服给药后，静脉咪达唑仑血药浓度-时间曲线下面积（AUC）的预测变化为2.6倍，与临床观察结果一致。尽管口服咪达唑仑AUC的平均预测变化5.3倍低于平均观察值，但仍在观察范围内。肠道CYP 3A活性对K-I、k（无效）和CYP 3A半衰期变化的敏感性低于肝脏CYP 3A。该基于半生理学的药代动力学模型结合了肠道和肝脏中的CYP 3A失活，可准确预测克拉霉素的非线性药代动力学以及克拉霉素与咪达唑仑之间观察到的DDI。此外，该模型框架可以应用于其他基于机制的抑制剂。
The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3A, as in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e. g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K-I and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 mu M for K-i and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K-I, k(inact), and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors.