title: 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, r2=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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, PO Box 100485, Gainesville, FL 32610, United States.
authors.forename: Juha
authors.initials: J
authors.lastname: Juntunen
authors.forename: Susruta
authors.initials: S
authors.lastname: Majumdar
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Sloan
mesh_terms: D020003:1-Octanol; D016208:Databases, Factual; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D010539:Permeability; D011355:Prodrugs / Q000737:chemistry*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D012995:Solubility; D012997:Solvents / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D011355:Prodrugs; D012997:Solvents; D014867:Water; D020003:1-Octanol