Abstract
The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3763–3772, 2011
Highlights
Drug absorption across the human intestinal wall occurs predominantly via passive transcellular diffusion
At the onset of this study, we wanted to investigate whether 2/4/A1 cell monolayers offer a suitable model for studies of passive drug transport in drug discovery and, for ranking of structural leads according to their permeability
We used a series of HIV-1 protease inhibitors (PIs) because these compounds present complex pharmacokinetic issues, and limited information is available regarding their structure–permeability and structure–efflux properties
Summary
Drug absorption across the human intestinal wall occurs predominantly via passive transcellular diffusion. For many drugs that are substrates for uptake and efflux of transport proteins in the intestinal epithelium, passive transport often contributes significantly to the total transport, in particular at Daisuke Nakai’s present address is Drug Metabolism and Pharmacokinetics Research Laboratories, Daiichi Sankyo Company, Ltd., Shinagawa-Ku, Tokyo, Japan. Whether this cell line would prove to be useful for permeability profiling in a drug discovery setting had not, as yet, been investigated
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