TRANSPORT OF METHOTREXATE DIALKYL ESTER PRODRUGS ACROSS FULL-THICKNESS HAIRLESS MOUSE SKIN

The permeability coefficients of methotrexate (MTX) and a series of it s mono and dialkyl ester prodrugs across full-thickness hairless mouse skin have been determined using an in vitro diffusion method. MTX was found to permeate across this skin model with a mean permeability of 5.6x10(-5) cm/hr. Monoesterification only slightly improved MTX permea tion and the effect appeared to be invariant with alkyl chain length. Diesterification of MTX, an the other hand, resulted in derivatives pr one to simultaneous conversion during permeation by both skin esterase and chemical hydrolysis in the diffusion medium. The contribution of conversion to overall MTX diffusion was treated mathematically in orde r to calculate the intrinsic permeabilities of MTX dialkyl esters. It was found that the dialkyl esters showed a parabolic permeability vers us chain length relationship with the dimethyl ester being the most pe rmeable compound.