Effect of barrier perturbation on cutaneous penetration of salicylic acid in hairless rats: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function.
The penetration of topically applied drugs is altered in diseased or barrier-damaged skin. We used microdialysis in the dermis to measure salicylic acid (SA) penetration in hairless rats following application to normal (unmodified) skin (n = 11) or skin with perturbed barrier function from (1) tape-stripping (n = 5), (2) sodium lauryl sulphate (SLS) 2% for 24 h (n = 3) or (3) delipidization by acetone (n = 4). Prior to the experiment, transepidermal water loss (TEWL) and erythema were measured. Two microdialysis probes were inserted into the dermis on the side of the trunk and 5% SA in ethanol was applied in a chamber overlying the probes. Microdialysis sampling was continued for 4 h, followed by measurements of probe depth by ultrasound scanning. SA was detectable in all samples and rapidly increasing up to 130 min. Microdialysates collected between 80 and 200 min showed mean SA concentrations of 3 microg/ml in unmodified and acetone-treated skin, whereas mean SA concentrations were 280 microg/ml in SLS-pretreated skin and 530 microg/ml in tape-stripped skin (P < 0.001). The penetration of SA correlated with barrier perturbation measured by TEWL (P < 0.001) and erythema (P < 0.001). A correlation between dermal probe depth and SA concentration was found in unmodified skin (P = 0.04). Microdialysis sampling in anatomical regions remote from the dosed site excluded the possibility that SA levels measured were due to systemic absorption. Microdialysis sampling of cutaneous penetration was highly reproducible. Impaired barrier function, caused by irritant dermatitis or tape stripping, resulted in an 80- to 170-fold increase in the drug level in the dermis. This dramatic increase in drug penetration could be relevant to humans, in particular to topical treatment of skin diseases and to occupational toxicology.
Benfeldt
E
E
Department of Dermatology, University of Copenhagen, Gentofte Hospital, Hellerup, Denmark. benfeldt@post5.tele.dk
Serup
J
J
D000042:Absorption; D000096:Acetone; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004890:Erythema / Q000378:metabolism; D005260:Female; D017551:Microdialysis; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020156:Salicylic Acid / Q000493:pharmacokinetics*; D012867:Skin / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D012871:Skin Diseases / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate; D012997:Solvents; D013501:Surface-Active Agents; D014463:Ultrasonography; D014870:Water Loss, Insensible
D012997:Solvents; D013501:Surface-Active Agents; D000096:Acetone; D012967:Sodium Dodecyl Sulfate; D020156:Salicylic Acid