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

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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.