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 dialk yl esters showed a parabolic permeability versus side chain length rel ationship with the dimethyl ester being the most permeable compound. T hese compounds were also found to undergo an increased degree of degra dation with increased ester chain length during the diffusion process, while with substantially reduced degradation occuring with the branch ed chain diisopropyl ester. No measurable methotrexate was formed duri ng the course of the experiment, apparently due to the chemical and en zymatic stability of the intermediate alpha- and gamma-monoesters.