title: Lipid synthesis inhibitors: effect on epidermal lipid conformational changes and percutaneous permeation of levodopa.
abstract: A combination of lipid synthesis inhibitors was used to enhance the in vitro and in vivo permeation of levodopa (LD) across rat epidermis, and their influence on epidermal lipids was investigated using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Rat epidermis was treated with ethanol and a combination of atorvastatin (750 microg/7 cm2), cerulenin (20 microg/7 cm2), and beta-chloroalanine (600 microg/7 cm2) for sustaining the reduced content of epidermal cholesterol, fatty acids (as triglycerides), and ceramide (as sphingosine), respectively, in viable rat skin. This treatment resulted in significant (P < .05) synthesis inhibition of skin lipids up to 48 hours and 6-fold enhancement in the in vitro permeation of LD. The effective plasma concentration of LD was achieved within 1 hour and maintained over 48 hours after topical application to rat epidermis treated with a combination of these lipid synthesis inhibitors. ATR-FTIR studies of inhibitor(s)-treated rat epidermis revealed a significant decrease (P < .05) in peak height and area for both asymmetric and symmetric C-H stretching absorbances, suggesting extraction of lipids. However, an insignificant (P < .05) shift in the frequency of these peaks suggested no fluidization of epidermal lipids by lipid synthesis inhibitors. A direct correlation was observed between epidermal lipid synthesis inhibition, decrease in peak height or area, and percutaneous permeation of LD. Skin lipid synthesis inhibition by a combination of lipid synthesis inhibitors seems to offer a feasible approach for enhancing the transcutaneous delivery of LD.
authors.affiliation: Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147 002, Punjab, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Babita
authors.forename: Vikas
authors.initials: V
authors.lastname: Rana
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Tiwary
mesh_terms: D000287:Administration, Topical; D000818:Animals; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D007980:Levodopa / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008055:Lipids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D017208:Rats, Wistar; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology*
chemical_list: D008055:Lipids; D007980:Levodopa