Impact of Ignoring Extraction Ratio When Predicting Drug-Drug Interactions, Fraction Metabolized, and Intestinal First-Pass Contribution
Impact of Ignoring Extraction Ratio When Predicting Drug-Drug Interactions, Fraction Metabolized, and Intestinal First-Pass Contribution
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DOI：
10.1124/dmd.110.034736
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发表时间：
2010-11-01
影响因子：
3.9
通讯作者：
Unadkat, Jashvant D.
中科院分区：
文献类型：
--
作者：
Kirby, Brian J.;Unadkat, Jashvant D.
许多数学模型的体外到体内预测药物相互作用（ddi）的口服受害者药物已经开发。然而，迄今为止，这些模型中没有一个适用于所有静脉给药的受害者药物。我们对现有的多模式相互作用预测模型进行了修改，使其适用于所有静脉给药的受害者药物，并对其进行了敏感性/误差分析。使用该模型，我们发现，忽略静脉给药药物的肝提取比（EH）（低至0.3）可能导致1)严重低估f（m, CYPi)（通过给定酶途径对给药药物的肝脏清除的比例）和2）在解剖ddi对口服给药药物的肠道和肝脏成分的贡献时出现错误。使用该模型，我们描述了DDI边界（抑制或诱导程度），在该边界上，忽略常用药物的EH会导致浓度-时间曲线（AUC）比例下的预测面积出现>= 30%的误差，或者肠道相互作用对DDI的贡献（仅限CYP3A探针）。对于最广泛使用的受害者药物咪达唑仑，AUC比值的边界为净抑制(I/K(I)或lambda/ K(deg)) >= 1.3或倍诱导>= 2.1；肠道贡献的边界分别为0.37和1.5。为了准确预测静脉AUC比率，肠道贡献，或f(m, CYPi) 1)所有诱导性ddi，无论受害者药物的EH如何，2)中度至强抑制ddi，即使EH是中等（>= 0.3），我们建议使用我们的模型。
Many mathematical models for in vitro to in vivo prediction of drug-drug interactions (DDIs) of orally administered victim drugs have been developed. However, to date, none of these models have been applicable to all intravenously administered victim drugs. We derived and conducted a sensitivity/error analysis of a modification to the existing multiple mode interaction prediction model such that it is applicable to all intravenously administered victim drugs. Using this model we showed that ignoring the hepatic extraction ratio (EH) (as low as 0.3) of intravenously administered victim drugs can result in 1) substantial underestimation of f(m, CYPi) (the fraction of hepatic clearance of the victim drug via a given enzymatic pathway) and 2) error in dissecting the contribution of intestinal and hepatic components of DDIs for orally administered drugs. Using this model we describe DDI boundaries (degree of inhibition or induction) at which ignoring the EH of commonly used victim drugs results in >= 30% error in the predicted area under the concentration-time curve (AUC) ratio or contribution of intestinal interaction to a DDI (CYP3A probes only). For the most widely used victim drug midazolam, these boundaries for AUC ratio are net inhibition (I/K(i) or lambda/k(deg)) >= 1.3 or fold induction >= 2.1; for intestinal contribution the boundaries are 0.37 and 1.5, respectively. To accurately predict the intravenous AUC ratio, intestinal contribution, or f(m, CYPi) 1) for all induction DDIs irrespective of EH of the victim drug and 2) for modest to potent inhibition DDIs even when the EH is moderate (>= 0.3), we propose that our model be used.