Discriminant analysis as a tool to identify compounds with potential as transdermal enhancers.
Structure-activity relationships were sought for 73 enhancers of hydrocortisone permeation from propylene glycol across hairless mouse skin. Enhancers had chain lengths (CC) from 0 to 16 carbon atoms, 1 to 8 H-bonding atoms (HB), molecular weight 60 to 450, log P (calculated) -1.7 to 9.7 and log S (calculated) -7.8 to 0.7. These predictive properties were chosen because of their ready availability. Enhancement ratio (ER) was defined as hydrocortisone transferred after 24 h relative to control. Values for the ER ranged from 0.2 to 25.3. Multiple regression analysis failed to predict activity; ER values for the 'good' enhancers (ER > 10) were underestimated. Simple guidelines suggested that high ER was associated with CC > 12 and HB 2-5. This was refined by multivariate analysis to identify significant predictors. Discriminant analysis using CC, HB, and molecular weight correctly assigned 11 of the 12 'good' enhancers (92%). The incorrectly assigned compound was a known, idiosyncratic Br compound. Seventeen of the 61 'poor' enhancers (28%) were incorrectly assigned but four could be considered marginal (ER > 8). The success of this simple approach in identifying potent enhancers suggested its potential in predicting novel enhancer activity.
Pugh
W J
WJ
Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, UK. pugh@cardiff.ac.uk
Wong
R
R
Falson
F
F
Michniak
B B
BB
Moss
G P
GP
D000279:Administration, Cutaneous; D000818:Animals; D016002:Discriminant Analysis; D006854:Hydrocortisone / Q000008:administration & dosage / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D051379:Mice; D008954:Models, Biological; D010539:Permeability / Q000187:drug effects; D025341:Principal Component Analysis; D012044:Regression Analysis; D012869:Skin Absorption / Q000187:drug effects*; D013329:Structure-Activity Relationship; D015262:Xenobiotics / Q000008:administration & dosage / Q000494:pharmacology*
D015262:Xenobiotics; D006854:Hydrocortisone