The effect of water solubility of solutes on their flux through human skin in vitro.
The Flynn database (n=97) for determining the effect of the physicochemical properties of solutes on their skin absorption has been edited to give a database for which the solubilities of the solutes in water, S(AQ), and their maximum fluxes from water through human skin in vitro, J(MAQ), are known or can be calculated (n=76). Data from the six major contributors to the original Flynn database have been included. Data for solutes, which were significantly ionized or for experiments using different thicknesses of skin were not excluded so that the edited database is as diverse as the original. The edited database was fit to five equations where the independent variables were solubility in octanol (S(OCT)) in water (S(AQ)) or molecular weight (MW), and combinations of those three variables; and the dependent variable was J(MAQ). The best fit was obtained from the Roberts-Sloan (RS) equation: logJ(MAQ)=x+ylogS(OCT)+(1-y)logS(AQ)-zMW, x=-3.00, y=0.73, z=0.0048, r(2)=0.934, S.D.=0.37 and F=274. This result is important because J (amount/area time) is the more clinically useful descriptor of permeation compared to P (distance/time); and because the identification of S(AQ) as a significant variable in predicting flux changes the design parameters for optimizing topical delivery of drugs from solubility in lipids (or partition coefficients between OCT and AQ, K(OCT:AQ)) and MW, to solubility in lipids, S(OCT), and in water, S(AQ), as well as MW.
Majumdar
Susruta
S
Department of Medicinal Chemistry, University of Florida, P.O. Box 100485, Gainesville, FL 32610, USA.
Thomas
Joshua
J
Wasdo
Scott
S
Sloan
Kenneth B
KB
D000700:Analgesics / Q000493:pharmacokinetics; D005227:Fatty Acids / Q000493:pharmacokinetics; D005233:Fatty Alcohols / Q000493:pharmacokinetics; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D009930:Organic Chemicals / Q000493:pharmacokinetics*; D010636:Phenols / Q000493:pharmacokinetics; D012867:Skin / Q000378:metabolism*; D012995:Solubility; D012996:Solutions / Q000493:pharmacokinetics*
D000700:Analgesics; D005227:Fatty Acids; D005233:Fatty Alcohols; D009930:Organic Chemicals; D010636:Phenols; D012996:Solutions; D006854:Hydrocortisone