A comparison of the fit of flux through hairless mouse skin from water data to three model equations.
Data for the delivery of total species containing parent drugs from water through hairless mouse skin by prodrugs, logJ(MMAQ), has been fitted to the Roberts-Sloan, RS, the Kasting-Smith-Cooper, KSC, and Magnusson-Anissimov-Cross-Roberts, MACR, equations. The RS model which contains a parameter for the dependence of flux on solubility in water, S(AQ), as well as solubility in the lipid isopropyl myristate, S(IPM), gave the best fit: logJ(MMAQ)=-2.30+0.575 logS(IPM)+0.425 logS(AQ)-0.0016MW, r(2)=0.903. The values for the coefficients to the parameters are quite similar to those obtained when the RS model was fit to flux of solutes from water through human skin, logJ(MHAQ). There was no trend in predicting the under or over-performance of prodrugs based on their fit to the RS model and whether they were more or less soluble than their parent drugs. There was an inverse dependence of logJ(MMAQ) on partition coefficients or permeability coefficients similar to that observed for logJ(MHAQ). The similarities in trends for results for logJ(MMAQ) and logJ(MHAQ) suggests that design directives obtained from mouse skin can be extended to design new prodrugs or select new drugs for delivery through human skin.
Wasdo
Scott C
SC
Department of Medicinal Chemistry, University of Florida, Gainesville, FL 32610, USA.
Juntunen
J
J
Devarajan
H
H
Sloan
K B
KB
D000818:Animals; D004058:Diffusion; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D008812:Mice, Hairless; D008954:Models, Biological; D009226:Myristates / Q000737:chemistry; D010539:Permeability; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics*; D012867:Skin / Q000378:metabolism; D012869:Skin Absorption; D012995:Solubility; D012997:Solvents / Q000737:chemistry
D009226:Myristates; D011355:Prodrugs; D012997:Solvents; C008205:isopropyl myristate