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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Stereoselective and Concentration-Dependent Polarized Epithelial Permeability of a Series of Phosphoramidate Triester Prodrugs of d4T: An in Vitro Study in Caco-2 and Madin-Darby Canine Kidney Cell Monolayers

Medicinal Chemistry Group (D.S., C.M.) and Pharmaceutical Cell Biology Group (L.E.K., M.G.), Welsh School of Pharmacy, Cardiff University, Cardiff, Wales

Nucleoside analogs are successful, widely used antiviral and anticancer therapeutics. Nucleotide prodrugs (i.e., pronucleotide) have increasingly been used to improve in vivo efficacy of nucleoside analogs. In this study, we evaluated the permeability of a series of phosphoramidate triester prodrugs of the anti-HIV drug 2',3'-didehydro-2',3'-dideoxythymidine across monolayers of Caco-2, Madin-Darby canine kidney (MDCKII) epithelial cell line, and its recombinant clone containing the human MDR1/P-gp gene (MDR1-MDCKII). Transport was studied in the apical-to-basolateral (A-B) and the basolateral-to-apical directions (B-A). The impact upon transport of differences in stereochemistry at the chiral phosphate center was evaluated. In the Caco-2 and MDCK models the A-B permeability was lower than expected based on the lipophilicity of the compounds, suggesting the involvement of a polarized efflux system and/or metabolic degradation in limiting the absorption of these ester-based prodrugs. Average permeability values through cell monolayers obtained in the A-B direction were lower than in the B-A direction. The inclusion of the P-glycoprotein (P-gp) inhibitor verapamil in the transport medium markedly increased the permeability in the A-B direction, whereas decreasing it in the opposite direction, suggesting an efflux mechanism mainly mediated by P-gp. Stereoselective permeability was significant for the most lipophilic compounds, where the diastereoisomer possessing the slower eluting time on a reverse-phase high-performance liquid chromatography column was transported through Caco-2 and MDCK monolayers at higher rate.

Address correspondence to: Christopher McGuigan, Welsh School of Pharmacy, University of Wales Cardiff, King Edward VII Ave., Cardiff CF10 3XF, Wales. E-mail: mcguigan{at}cf.ac.uk

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