Transport of Cosalane—A Highly Lipophilic Novel Anti‐HIV Agent—Across Caco‐2 Cell Monolayers

Abstract

Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, the oral bioavailability of this highly lipophilic compound is extremely poor (<1%). Also, cosalane accumulates in high concentration in the liver after intravenous administration, with clear resistance to hepatic metabolism. In the present study, the transcellular permeability of cosalane was examined using Transwell® filter as well as plastic‐grown confluent Caco‐2 cell monolayers. A cell‐culture‐based biophysical model was adopted to understand the interactions of protein binding, membrane partitioning, and aqueous solubility of cosalane in limiting transcellular flux of cosalane across Caco‐2 cell monolayers. The transcellular permeability (Papp) of cosalane was extremely low (4.494 × 10−8 cm/s) and the effect of p‐glycoprotein on the efflux of cosalane was negligible. A characteristic disparity exists between the kinetics of cosalane uptake from apical (AP) donor solution and efflux into basolateral (BL) receiver side. The AP uptake of cosalane was rapid, exhibiting exponential kinetics, and reached equilibrium within 60 min, whereas the concomitant appearance of the compound into the BL receiver side was slow but linear over time. Furthermore, the uptake of cosalane was significantly reduced in the presence of bovine serum albumin (BSA). In unidirectional efflux studies, AP efflux of cosalane was limited in the absence of BSA. Also, no detectable metabolites were found in Caco‐2 cell incubations. In conclusion, the present study demonstrates that diffusion of cosalane across Caco‐2 cell monolayers is extremely limited and kinetically regulated essentially by the equilibrium between protein‐bound and free drug partitioning into cell membrane. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89:826–833, 2000