Effect of vehicle pretreatment on the flux, retention, and diffusion of topically applied penetrants in vitro.
OBJECTIVE
The flux of a topically applied drug depends on the activity in the skin and the interaction between the vehicle and skin. Permeation of vehicle into the skin can alter the activity of drug and the properties of the skin barrier. The aim of this in vitro study was to separate and quantify these effects.


METHODS
The flux of four radiolabeled permeants (water, phenol, diflunisal, and diazepam) with log Koct/water values from 1.4 to 4.3 was measured over 4 h through heat-separated human epidermis pretreated for 30 min with vehicles having Hildebrand solubility parameters from 7.9 to 23.4 (cal/cm3)1/2.


RESULTS
Enhancement was greatest after pretreatment with the more lipophilic vehicles. A synergistic enhancement was observed using binary mixtures. The flux of diazepam was not enhanced to the same extent as the other permeants, possibly because its partitioning into the epidermis is close to optimal (log Koct 2.96).


CONCLUSIONS
An analysis of the permeant remaining in the epidermis revealed that the enhancement can be the result of either increased partitioning of permeant into the epidermis or an increasing diffusivity of permeants through the epidermis.
Skin Research Centre, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, United Kingdom. crosado@ff.ul.pt
Catarina
C
Rosado
Sheree E
SE
Cross
W John
WJ
Pugh
Michael S
MS
Roberts
Jonathan
J
Hadgraft
D000279:Administration, Cutaneous; D003975:Diazepam / Q000008:administration & dosage / Q000493:pharmacokinetics; D004061:Diflunisal / Q000008:administration & dosage / Q000493:pharmacokinetics; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000494:pharmacology*; D019800:Phenol / Q000008:administration & dosage / Q000493:pharmacokinetics; D012869:Skin Absorption / Q000187:drug effects*; D014867:Water
D014677:Pharmaceutical Vehicles; D014867:Water; D019800:Phenol; D004061:Diflunisal; D003975:Diazepam