The effect of water solubility of solutes on their flux through human skin in vitro:: A prodrug database integrated into the extended Flynn database

A database (n=50) consisting of values of solubility in water, S-AQ, solubility in octanol, S-OCT, molecular weight, MW, and maximum flux based on the delivery of total species containing a parent drug by its prodrugs through human skin in vitro from water has been integrated into the extended Flynn database (n=114). In addition, data for two more recent contributions (n=8) and one (n=7) contribution that was overlooked for inclusion in the extended Flynn database were added to the prodrug database, as well as the data for the parent drugs (n=6), to give n=71 and n=185 for the total integrated database. This integrated database was fit to five equations where the independent variable was SAQ, SOCT or MW alone or were combinations of S-OCT and MW (Kasting-Smith-Cooper, KSC model) or SOCT, SAQ and MW (Roberts-Sloan, RS model). The RS equation gave the best fit: log J(MAQ) = -2.506 + 0.538 log S-OCT + 0.462 log S-AQ -0.00402MW, r(2) = 0.839, S.D. = 0.423 and the residual (Delta log J(MAQ)) was 0.474 log units. Integration of a substantial number of prodrugs into the extended Flynn database did not change the dependence of J(MAQ) on a balance of S-AQ and S-OCT. No trend in the effect of the prodrug being more or less water soluble than its parent drug on over- or underpredicting flux (+/-Delta'log J(MAQ)) by the RS model was found. Thus optimization of the S-AQ of a prodrug in its design, as well as the design of new drugs, is indicated. (C) 2007 Elsevier B.V. All rights reserved.