Quantiative prediction of intestinal availability of CYP3A4 substrates

基于人肠道微生物体的体外代谢研究和Caco-2细胞的外排研究，定量预测了CYP3A4底物的肠道利用度。以阿普唑仑(ALP)、三唑仑(TRZ)、咪达唑仑(MDZ)、卡马西平(CBZ)和睾酮(TST)为模型底物。根据单室动力学模型预测了药物在肠腔内的转运、肠上皮细胞的吸收、上皮细胞内的代谢和门静脉流出的模型：肠转运、吸收和代谢(ITAM)模型，并根据单室动力学模型预测了ALP、TRZ和CBZ的Fg值。然而，预测的MDZ的Fg比报道的人类Fg要小。鉴于已有报道MDZ在CYP3A4表达系统中表现出机制抑制物样特征，我们研究了MDZ在人类肠道微粒体中是否表现出机制抑制物样特征。MDZ在人的肠道微粒体中确实表现出机制抑制物样特征，并用具有机制抑制物样特征的ITAM模型预测了MDZ的Fg。MDZ的Fg预测值与报道值接近，表明MDZ在上皮细胞中是一种基于机制的抑制物，在吸收过程中MDZ本身的代谢受到抑制。

Intestinal availability (Fg) of CYP3A4 substrates were quantitatively predicted based on the in vitro metabolic study with human intestinal microsomes and the efflux study with Caco-2 cells. Alprazolm (ALP), triazolam (TRZ), midazolam (MDZ), carbamazepine (CBZ) and testosterone (TST) were used as model CYP3A4 substrates. Fg values were predicted according to the single compartment kinetic model, and the more precise model was also developed which incorporated the transit of the drug in the intestinal lumen, absorption into the intestinal epithelial cells, the metabolism in the epithelial cells and the exit to the portal vein: Intestinal Transit, Absorption and Metabolism (ITAM) model.Fg values of ALP, TRZ and CBZ were well predicted according to the single compartment kinetic model. However, the predicted Fg of MDZ was smaller than the reported Fg in humans. Since it has been reported that MDZ shows mechanism-based inhibitor like characteristics in CYP3A4 expression system, we studied if MDZ exhibits mechanism-based inhibitor like characteristics in human intestinal microsomes. MDZ did exhibit mechanism-based inhibitor like characteristics in human intestinal microsomes, and the Fg of MDZ was predicted using an ITAM model with mechanism based inhibitor like characteristics. The predicted Fg value of MDZ became close to the reported value, which indicated that MDZ acts as a mechanism-based inhibitor in the epithelial cells and that the metabolism of MDZ itself is inhibited in the process of absorption.