TRANSPORT AND DEGRADATION CHARACTERISTICS OF METHOTREXATE DIALKYL ESTER PRODRUGS ACROSS TAPE-STRIPPED HAIRLESS MOUSE SKIN

A series of methotrexate dialkyl esters were examined with respect to their permeability across tape-stripped hairless mouse skin. The dialkyl esters showed a parabolic permeability versus side chain length relationship with the dimethyl ester being the most permeable compound. These compounds were also found to undergo an increased degree of degradation with increased ester chain length during the diffusion process, while with substantially reduced degradation occuring with the branched chain diisopropyl ester. No measurable methotrexate was formed during the course of the experiment, apparently due to the chemical and enzymatic stability of the intermediate alpha- and gamma-monoesters.