Quantitative prediction of oral absorption of PEPT1 substrates based on in vitro uptake into Caco-2 cells

Abstract

The method for predicting the fraction absorbed ( F a) 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 (ΔCL 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 ΔCL uptake of each drug was then divided by that of cephradine to obtain Δ C L uptake ∗ , 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 Δ C L uptake ∗ and F a 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, F a was predicted from the Δ C L uptake ∗ value of each drug. Good correlation was observed between the predicted and reported F a values, which demonstrated that F a of PEPT1 substrates can be predicted based on the in vitro uptake in Caco-2 cells.