Ripp Sharon L, Mills Jessica B, Fahmi Odette A, Trevena Kristen A, Liras Jennifer L, Maurer Tristan S, de Morais Sonia M
Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA.
Drug Metab Dispos. 2006 Oct;34(10):1742-8. doi: 10.1124/dmd.106.010132. Epub 2006 Jul 12.
Cytochrome P4503A4 (CYP3A4) is the principal drug-metabolizing enzyme in human liver. Drug-drug interactions (DDIs) caused by induction of CYP3A4 can result in decreased exposure to coadministered drugs, with potential loss of efficacy. Immortalized hepatocytes (Fa2N-4 cells) have been proposed as a tool to identify CYP3A4 inducers. The purpose of the current studies was to characterize the effect of known inducers on CYP3A4 in Fa2N-4 cells, and to determine whether these in vitro data could reliably project the magnitude of DDIs caused by induction. Twenty-four compounds were chosen for these studies, based on previously published data using primary human hepatocytes. Eighteen compounds had been shown to be positive for induction, and six compounds had been shown to be negative for induction. In Fa2N-4 cells, all 18 positive controls produced greater than 2-fold maximal CYP3A4 induction, and all 6 negative controls produced less than 1.5-fold maximal CYP3A4 induction. Subsequent studies were conducted to determine the relationship between in vitro induction data and in vivo induction response. The approach was to relate in vitro induction data (E(max) and EC(50) values) with efficacious free plasma concentrations to calculate a relative induction score. This score was then correlated with decreases in area under the plasma concentration versus time curve values for coadministered CYP3A4 object drugs (midazolam or ethinylestradiol) from previously published clinical DDI studies. Excellent correlations (r(2) values >0.92) were obtained, suggesting that Fa2N-4 cells can be used for identification of inducers as well as prediction of the magnitude of clinical DDIs.
细胞色素P4503A4（CYP3A4）是人类肝脏中主要的药物代谢酶。由CYP3A4诱导引起的药物-药物相互作用（DDIs）可导致同时服用的药物暴露减少，可能会失去疗效。永生化肝细胞（Fa2N-4细胞）已被提议作为一种识别CYP3A4诱导剂的工具。当前研究的目的是表征已知诱导剂对Fa2N-4细胞中CYP3A4的影响，并确定这些体外数据是否能够可靠地预测由诱导引起的DDIs的程度。基于先前使用原代人肝细胞发表的数据，选择了24种化合物进行这些研究。18种化合物已被证明诱导呈阳性，6种化合物已被证明诱导呈阴性。在Fa2N-4细胞中，所有18种阳性对照产生的CYP3A4最大诱导倍数均大于2倍，所有6种阴性对照产生的CYP3A4最大诱导倍数均小于1.5倍。随后进行了研究以确定体外诱导数据与体内诱导反应之间的关系。方法是将体外诱导数据（E(max)和EC(50)值）与有效游离血浆浓度相关联，以计算相对诱导分数。然后将该分数与先前发表的临床DDI研究中同时服用的CYP3A4目标药物（咪达唑仑或炔雌醇）的血浆浓度-时间曲线下面积值的降低相关联。获得了极好的相关性（r(2)值>0.92），表明Fa2N-4细胞可用于识别诱导剂以及预测临床DDIs的程度。
