Prediction of Oral Absorption of Anionic Drugs that are Absorbed by the Monocarboxylic Acid Transport System

本研究表明，某些青霉素类药物(环孢西林、阿莫西林和氨苄西林)和头孢菌素类药物(头孢拉定、头孢克洛、头孢氨苄、头孢布烯、头孢克辛、头孢替安和头孢唑林)的口服吸收可根据Caco-2细胞的体外吸收情况进行定量预测。在没有或存在30 mM甘氨酰肌氨酸(Gly-Sar)的情况下，在pH 6.0下测量药物在Caco-2细胞中的摄取。计算PEPT1的初始摄取清除量(ΔCL&lt；摄取&gt；)为无Gly-Sar时摄取清除量与30 mM Gly-Sar时摄取清除量之差。为了校正日间和/或细胞间的变异性，然后将每种药物的ΔCL；摄取量除以头孢拉定的摄取量，得到ΔCL摄取量。根据完全径向混合模型，利用ΔCL&lt；吸收&gt；^*公式计算了吸收分数(Fa)。观察到的FA值与预测的FA值之间有很好的相关性，也可以根据PEPT1表达细胞(HeLa-PEPT1细胞)的体外吸收来预测这些药物的口服吸收。预测FA的方法与上述相同，只是Δ的摄取和摄取是根据HeLaPEPT1细胞摄取和模拟细胞摄取的差值来计算的。卡托普利是一种血管紧张素转换酶抑制剂，据信可通过PEPT1吸收。当Caco-2细胞被用于目前的预测时，其他转运体可能参与药物的摄取，这可能导致对口服吸收的高估。我们预计，目前的HeLa-PEPT1细胞预测方法将被改进，以筛选大量PEPT1介导的吸收候选药物。

It was shown in the present study that oral absorption of some penicillins (cyclacillin, amoxicillin and ampicillin) and cephems (cephradine, cefaclor, cephalexin, ceftibuten, cefixime, cefotiam and cefazolin) can be quantitatively predicted based on in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured at pH 6.0 in the absence or presence of 30 mM glycyl-sarcosine (Gly-Sar). Initial uptake clearance by PEPT1 (ΔCL_<uptake>) was calculated as the difference between the uptake clearance in the absence of Gly-Sar and that in the presence of 30 mM Gly-Sar. In order to correct for inter-day and/or inter-cell variability, the ΔCL_<uptake> of each drug was then divided by that of cephradine to obtain ΔCL_<uptake>^*. Using the ΔCL_<uptake>^*, the fraction absorbed (Fa) was calculated according to the equation derived from the complete radial mixing (CRM) model. Good correlation was observed between the observed and predicted Fa values.Oral absorption of these drugs can also be predicted based on in vitro uptake into PEPT1-expressing cells (HeLa-PEPT1 cells). Fa was predicted in the same manner as described above except that ΔCL_<uptake> was calculated as the difference between the uptake into HeLa-PEPT1 cells and that into mock cells.In HeLa-PEPT1 cells, however, it was demonstrated that captopril was not transported by PEPT1. Captopril is an ACE inhibitor that has been believed to be absorbed via PEPT1. When Caco-2 cells are used in the present prediction, other transporters may be involved for uptake of drugs, which may result in over-estimate of oral absorption. We expect that the present prediction method with HeLa-PEPT1 cells will be improved for screening a large number of drug candidates for PEPT1-mediated absorption.