Prediction of in vivo drug-drug interactions from in vitro data:: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant
Prediction of in vivo drug-drug interactions from in vitro data:: impact of incorporating parallel pathways of drug elimination and inhibitor absorption rate constant
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DOI：
10.1111/j.1365-2125.2005.02483.x
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发表时间：
2005-11-01
影响因子：
3.4
通讯作者：
Houston, JB
中科院分区：
文献类型：
--
作者：
Brown, HS;Ito, K;Houston, JB
目的通过酶活性位点抑制剂浓度（[I]）和体外抑制常数（Ki）定量预测CYP介导代谢抑制的药物间相互作用的成功率是可变的。本研究的目的是研究的影响的受害者药物代谢的一个特定的代谢物（f（mglutamine））和抑制剂的吸收速率常数（k（a））上的预测accuracy.MethodsDrug-drug interaction studies involving inhibition of CYP 2C 9，CYP 2D 6和CYP 3A 4（n = 115）进行了调查。将每种酶的探针底物的f（mf）和抑制剂的k（a）值数据单独或组合纳入体内预测中，使用最大肝脏输入或平均全身血浆浓度作为[I]的替代。预测的成功（AUC比预测在体内值的两倍内）进行了比较，使用标称值f（mean）= 1和k（a）= 0.1 min（-1）。ResultsThe纳入f（mean）值到体内预测使用肝输入血浆浓度导致在体内值的两倍内的研究的84%。单独k（a）值的影响显著减少了CYP 2D 6和CYP 3A 4的过度预测数量;然而，与f（mean）相比，观察到的精密度较低。合并的f（mglutamine）和k（a）值导致在81%的研究内的两倍，在vivo value.ConclusionsThe纳入的底物和代谢相关的信息，即f（mglutamine）和k（a），显着提高预测的115个相互作用的研究与CYP 2C 9，CYP 2D 6和CYP 3A 4相比，[I]/K-i比率单独。
AimsSuccess of the quantitative prediction of drug-drug interactions via inhibition of CYP-mediated metabolism from the inhibitor concentration at the enzyme active site ([I]) and the in vitro inhibition constant (K-i) is variable. The aim of this study was to examine the impact of the fraction of victim drug metabolized by a particular CYP (f(mCYP)) and the inhibitor absorption rate constant (k(a)) on prediction accuracy.MethodsDrug-drug interaction studies involving inhibition of CYP2C9, CYP2D6 and CYP3A4 (n = 115) were investigated. Data on f(mCYP) for the probe substrates of each enzyme and k(a) values for the inhibitors were incorporated into in vivo predictions, alone or in combination, using either the maximum hepatic input or the average systemic plasma concentration as a surrogate for [I]. The success of prediction (AUC ratio predicted within twofold of in vivo value) was compared using nominal values of f(mCYP) = 1 and k(a) = 0.1 min(-1).ResultsThe incorporation of f(mCYP) values into in vivo predictions using the hepatic input plasma concentration resulted in 84% of studies within twofold of in vivo value. The effect of k(a) values alone significantly reduced the number of over-predictions for CYP2D6 and CYP3A4; however, less precision was observed compared with the f(mCYP). The incorporation of both f(mCYP) and k(a) values resulted in 81% of studies within twofold of in vivo value.ConclusionsThe incorporation of substrate and inhibitor-related information, namely f(mCYP) and k(a), markedly improved prediction of 115 interaction studies with CYP2C9, CYP2D6 and CYP3A4 in comparison with [I]/K-i ratio alone.