Permeability evaluation of peptidic HCV protease inhibitors in Caco-2 cells-correlation with in vivo absorption predicted in humans

Abstract The permeability of six peptidic hepatitis C virus (HCV) protease inhibitors, with molecular weights ranging from 500 to 780, was examined in the Caco-2 cell system. All six compounds permeated the cells transcellularly; paracellular permeability, evaluated in the Caco-2 cell system by reducing the calcium concentration in the media to increase the pore size of the tight junctions, most likely contributes only minimally to the oral absorption of the compounds. All six compounds were shown to be efflux substrates displaying concentration-dependent saturation of efflux. The efflux could be blocked by cyclosporine A, a specific P-glycoprotein (P-gp) inhibitor, suggesting that P-gp may be the responsible transporter. Oral absorption in rats was calculated using in vivo oral bioavailability and hepatic extraction ratios. Human oral absorption was projected to be similar to that of rats, as reported previously by comparing rat and human absorption values for 23 marketed drugs. Upon comparison of human oral absorption predicted by Caco-2 permeability and by rat pharmacokinetics, we show a better correlation with Caco-2 permeability obtained at higher compound concentrations, where efflux is saturated, than at lower concentrations. The higher concentrations are likely reflecting the lumen concentrations after in vivo oral dosing. The results presented in this study demonstrate that, when tested at relevant compound concentrations, Caco-2 permeability is useful for predicting the oral absorption of peptidic compounds.