Feasibility of measuring lipophilic or protein-bound drugs in the dermis by in vivo microdialysis after topical or systemic drug administration.
Our aim was to assess the microdialysis technique for determining in vivo drug levels of a lipophilic and a protein-bound model drug in the dermis. Forearm skin of healthy volunteers received topical 2% fusidic acid or 0.1% betamethasone-17-valerate formulations twice daily as occluded treatment on irritative dermatitis. Microdialysis sampling in the dermis after 48 h was without measurable drug. Hairless rats received maximized treatment with occluded applications of 10% fusidic acid or 4% betamethasone-17-valerate in ethanol for 72 h followed by microdialysis. Mean levels of betamethasone-17-valerate were 11-45 ng/ml; fusidic acid was not measurable. Systemic administration in clinical doses to rats was without measurable drug levels; increasing doses to 312 mg/kg of fusidic acid and 158 mg/kg of betamethasone-17-valerate yielded betamethasone-17-valerate levels of 25-44 ng/ml and fusidic acid levels of 10-90 ng/ml. This study demonstrates the challenges arising when using microdialysis for measuring in vivo-drug levels. For the drugs chosen it was necessary to administer very high systemic doses or apply a high topical drug concentration to obtain measurable drug levels in the dialysates. Drug levels were in the nanomolar range and demonstrated reproducible and dynamic monitoring of in vivo drug levels in the skin. Using microdialysis for sampling highly protein-bound or lipophilic drugs in the skin requires very sensitive analytical methods, and the sensitivity of the analysis is likely to be the limiting factor.
Department of Dermatology, University of Copenhagen, Gentofte Hospital, Hellerup, Denmark.
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Benfeldt
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Groth
D000284:Administration, Oral; D000287:Administration, Topical; D000328:Adult; D000818:Animals; D001623:Betamethasone / Q000008:administration & dosage / Q000032:analysis*; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005260:Female; D005672:Fusidic Acid / Q000008:administration & dosage / Q000032:analysis*; D006801:Humans; D008297:Male; D017551:Microdialysis / Q000379:methods*; D010328:Patch Tests; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D012867:Skin / Q000737:chemistry*; D012869:Skin Absorption / Q000187:drug effects; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D013501:Surface-Active Agents / Q000494:pharmacology
D011500:Protein Synthesis Inhibitors; D013501:Surface-Active Agents; D012967:Sodium Dodecyl Sulfate; D005672:Fusidic Acid; D001623:Betamethasone