Effects of calcium and lipophilicity on transport of clodronate and its esters through Caco-2 cells

Clodronate, like other bisphosphonates, is poorly absorbed from the gastroi ntestinal tract, mainly due to its high hydrophilicity and ability to form complexes with divalent cations in the gastrointestinal tract. One strategy for improving oral absorption of these types of molecules is to develop mo re lipophilic derivatives. The importance of lipophilicity and calcium chel ation in the absorption of clodronate was evaluated by studying the penetra tion of clodronate and its mono-, di-, and triphenyl esters through human i ntestinal Caco-2 cells. The transport rates of [C-14]-clodronate and its mo no-, di-, and triphenyl esters were quantified by calculating their apparen t permeability coefficients (P-app) both in normal (1.3 mM) calcium concent ration and in 'minimum-calcium model'. The transport rate of 1 mM clodronat e was very low (0.25 x 10(-7) cm/s), while the removal of calcium from the apical side increased this transport rate B-fold. The transport rate of clo dronate was increased with increasing dose. Mono- and diphenyl esters did n ot significantly enhance the transport of clodronate. Triphenyl ester, howe ver, increased the transport rate 17-fold compared with parent clodronate. Removal of calcium did not affect the transport rates of di- or triphenyl e sters, which indicated that the esterification of hydroxyl groups of clodro nate decreased calcium complex formation. These results indicate that clodr onate is transported paracellularly through Caco-2 cells and that calcium d ecreases strongly its absorption. They further suggest that at least three phosphate hydroxyl groups need to be substituted until the permeation route is changed from paracellular to transcellular. (C) 2001 Elsevier Science B .V. All rights reserved.