Shimizu Rikako, Sukegawa Tomomi, Tsuda Yasuyuki, Itoh Tomoo
School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Int J Pharm. 2008 Apr 16;354(1-2):104-10. doi: 10.1016/j.ijpharm.2007.12.045. Epub 2008 Jan 11.
The method for predicting the fraction absorbed (Fa) of the PEPT1 substrates was established based on the in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured, and the carrier-mediated initial uptake clearance (DeltaCL uptake) was calculated as the difference between the uptake clearance in the absence of glycyl-sarcosine (Gly-Sar) and that in the presence of 30 mM Gly-Sar. The DeltaCL uptake of each drug was then divided by that of cephradine to obtain DeltaCLuptake, which was a normalized parameter to correct for inter-day and/or inter-cell variability. Then, cephradine (CED), cefixime (CFIX), and cefotiam (CTM) were selected as marker compounds having excellent, medium and poor absorption, respectively. The DeltaCLuptake and Fa values for CED, CFIX and CTM were fitted to the equation derived from the complete radial mixing (CRM) model, and the scaling factor (A') was obtained. Using the A' value, Fa was predicted from the DeltaCL*uptake value of each drug. Good correlation was observed between the predicted and reported Fa values, which demonstrated that Fa of PEPT1 substrates can be predicted based on the in vitro uptake in Caco-2 cells.
基于药物在体外被Caco-2细胞摄取的情况，建立了预测肽转运体1（PEPT1）底物吸收分数（Fa）的方法。测定药物进入Caco-2细胞的摄取量，并计算载体介导的初始摄取清除率（ΔCL摄取），其为在不存在甘氨酰肌氨酸（Gly-Sar）时的摄取清除率与在存在30 mM Gly-Sar时的摄取清除率之间的差值。然后将每种药物的ΔCL摄取除以头孢拉定的ΔCL摄取，以获得ΔCL摄取，这是一个用于校正日间和/或细胞间变异性的标准化参数。接着，分别选择头孢拉定（CED）、头孢克肟（CFIX）和头孢替安（CTM）作为吸收良好、中等和较差的标记化合物。将CED、CFIX和CTM的ΔCL摄取值和Fa值拟合到由完全径向混合（CRM）模型推导的方程中，从而获得比例因子（A'）。利用A'值，根据每种药物的ΔCL*摄取值预测Fa。预测的Fa值与报道的Fa值之间观察到良好的相关性，这表明可以基于药物在Caco-2细胞中的体外摄取来预测PEPT1底物的Fa。
