Effect of barrier perturbation on cutaneous salicylic acid penetration in human skis: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function

We have used microdialysis in the dermis for assessing penetration kinetics of salicylic acid (SA) in healthy volunteers (n = 18), following applicati on on the volar aspect of the left forearm. Penetration was monitored at fo ur locations: in normal (unmodified) skin and in skin with perturbed barrie r function from (i) repeated tape stripping (ii) irritant dermatitis from 1 or 2% sodium lauryl sulphate (SLS) for 24 h and (iii) delipidization by ac etone. The order of the treatments was randomized according to a latin squa re design, Epidermal barrier function and skin irritation were assessed in each location using evaporimetry and colorimetry. Transepidermal water loss (TEWL) values confirmed that both mild (acetone), moderate (1% SLS) and se vere barrier damage (tape stripping and 2% SLS) had occurred. Microdialysis sampling with two parallel probes in the dermis was performed in each of t he four treatment areas for every subject. SA (5% in ethanol) was applied i n a chamber glued to the skin overlying the microdialysis probes and sampli ng was continued for 4 h. SA was detectable in all samples and measurable i n all samples from penetration through perturbed skin. Comparing the SA pen etration in barrier-perturbed skin with the penetration in unmodified skin in the same subject, the mean SA penetration increase was 2.2-fold in aceto ne-treated skin (P = 0.012), 46-fold in mild dermatitis and 146- and 157-fo ld in severe dermatitis and tape stripped skin, respectively (P < 0.001). T he penetration of SA significantly correlated with the measurements of barr ier perturbation by TEWL (P = 0.01) and erythema (P = 0.02) for each indivi dual. Microdialysis sampling of SA penetration was more sensitive than non- invasive measuring techniques in detecting significant barrier perturbation in acetone-treated skin. A positive dose-response relationship for the per cutaneous penetration of SA in response to increasing SLS pretreatment conc entrations and thus the degree of irritant dermatitis was found. When analy sing data by location on the forearm, a tendency towards an intraregional v ariation in the reactivity to barrier damage was found, with the most proxi mal location displaying higher reactivity scores than the most distal locat ion in response to the same barrier perturbation procedures. The penetratio n of SA was not significantly different between locations. In conclusion, u sing microdialysis in the dermis to obtain real-time dermal pharmacokinetic s in the target organ, this study demonstrates highly increased and differe ntiated cutaneous penetration of SA in barrier-perturbed skin. The measured drug penetration was demonstrated to correlate with non-invasive quantific ation of barrier damage.