Pre-clinical Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
Curr Drug Metab. 2010 Nov;11(9):762-77. doi: 10.2174/138920010794328922.
Recently, interest has grown in drug-drug interactions (DDIs) involving the inhibition of intestinal CYP3A4, P-glycoprotein (P-gp), and other drug efflux transporters. The criteria for intestinal DDIs are described in the draft guidances of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). Substrate drugs with small fraction absorbed (Fa) and/or low intestinal availability (Fg) as a result of intestinal efflux transport and metabolism are important as "victim" drugs because these substrates are likely to show considerable interactions. The susceptibility of a victim drug to intestinal interactions can be evaluated from its FaFg. In this review, methods for estimating the FaFg of substrate drugs are discussed. The nonlinear pharmacokinetics of substrate drugs caused by the saturation of intestinal CYP3A4/P-gp is also discussed. The methods for predicting intestinal DDIs caused by inhibitor drugs are then summarized. Because the prediction accuracy of intestinal DDIs also depends on the inhibition constant (Ki) estimated in in vitro studies, these in vitro methods of estimating Ki are also discussed. Standardized methods for predicting intestinal DDIs have not yet been established. Further studies are required to establish more accurate and standardized prediction methods.
最近，人们对涉及抑制肠道 CYP3A4、P-糖蛋白（P-gp）和其他药物外排转运体的药物-药物相互作用（DDI）产生了浓厚的兴趣。美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）的指导草案中描述了肠道 DDI 的标准。由于肠道外排转运和代谢，吸收分数（Fa）小和/或肠道利用率（Fg）低的底物药物是重要的“受害者”药物，因为这些底物很可能会表现出相当大的相互作用。可以从 FaFg 评估易受肠道相互作用影响的受害药物的敏感性。在这篇综述中，讨论了估计底物药物 FaFg 的方法。还讨论了由于肠道 CYP3A4/P-gp 饱和而导致的底物药物的非线性药代动力学。然后总结了预测抑制剂药物引起的肠道 DDI 的方法。由于肠道 DDI 的预测准确性还取决于在体外研究中估计的抑制常数（Ki），因此还讨论了这些用于估计 Ki 的体外方法。尚未建立预测肠道 DDI 的标准化方法。需要进一步的研究来建立更准确和标准化的预测方法。
