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

Abstract 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 S AQ , S OCT or MW alone or were combinations of S OCT and MW (Kasting–Smith–Cooper, KSC model) or S OCT , S AQ 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 (Δlog  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 (±Δ′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.