Epidermal lipids: thermotropic behavior and role in transcutaneous permeation of levodopa

Abstract

AbstractSkin lipids play a pivotal role in maintaining the barrier properties of skin. The present investigation aimed at studying the effect of skin lipid synthesis inhibitors on the transcutaneous delivery of levodopa (LD). Skin perturbation with ethanol was found to reduce the content of cholesterol, fatty acid, and sphingosine. Subsequent treatment with various doses of their respective synthesis inhibitors atorvastatin, cerulenin, and β‐chloroalanine sustained the reduced content of these lipids in viable rat skin. A maximum synthesis inhibition of approximately 80, 60, and 55% for cholesterol, triglycerides (an indicator of fatty acid), and sphingosine (a precursor of ceramide) was observed at 2, 2, and 8 h, respectively, after topical application of optimized dose of the inhibitors. Differential scanning calorimetric (DSC) analysis of treated rat epidermis revealed approximately 70, 52, and 50% reduction in enthalpy (ΔH) of the lipid endothermic transition peak by the corresponding doses of inhibitors. The effective plasma concentration (Ceff) of LD in rats was achieved by treatment with atorvastatin, cerulenin, and β‐chloroalanine within 2, 4, and 6 h, respectively. After application of a combination of these inhibitors, the lag time was reduced to 1 h and Ceff was maintained over 48 h. The inhibition of lipid synthesis in epidermis and concomitant decrease in enthalpy of lipid endothermic transition were directly correlated with enhanced in vitro and in vivo permeation of LD. These findings suggest that lipid synthesis inhibition can be exploited to enhance transcutaneous delivery of a polar drug, levodopa. Drug Dev Res 63:190–199, 2004. © 2004 Wiley‐Liss, Inc.