Transdermal delivery of zidovudine: effect of terpenes and their mechanism of action.
The effect of various oxygen-containing monoterpenes such as cineole, menthol, alpha-terpineol, menthone, pulegone and carvone was investigated on ex vivo permeation of zidovudine (AZT) across rat skin. Furthermore, saturation solubility of AZT, its stratum corneum (SC)/vehicle partition coefficient and activation energy for diffusion across skin with or without terpene(s) in vehicle (66.6% ethanol in water) were determined to understand their mechanism of action. All the terpenes studied significantly increased transdermal flux of AZT in comparison to vehicle (p<0.05) and their enhancement activities are in the following decreasing order: cineole>menthol>menthone approximately pulegone approximately alpha-terpineol>carvone>vehiclewater. On the other hand, saturation solubility and SC/vehicle partition coefficient of AZT were not significantly altered (p>0.05) by terpenes. Activation energies of AZT permeation across rat skin from water, vehicle and cineole in vehicle were measured to be 20.4, 18.6 and 10.6 kcal/mol, respectively. Interactions between terpenes and SC lipids were studied with molecular modeling and found that terpenes form hydrogen bonds (bond lengths<2 A) with lipid head groups. The mechanism of permeation enhancement of AZT by terpenes was explained with thermodynamic activity, SC/vehicle partition coefficient, activation energy and molecular modeling studies.
Narishetty
Sunil Thomas Kumar
ST
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) Sector 67, Phase 10, Mohali-160062, Punjab, India.
Panchagnula
Ramesh
R
D000277:Adjuvants, Pharmaceutic / Q000737:chemistry / Q000493:pharmacokinetics / Q000592:standards; D000279:Administration, Cutaneous; D000465:Algorithms; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004058:Diffusion; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000592:standards; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000431:Ethanol / Q000737:chemistry / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry; D007194:India; D008297:Male; D008954:Models, Biological; D039821:Monoterpenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000592:standards; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012869:Skin Absorption / Q000187:drug effects / Q000502:physiology; D013816:Thermodynamics; D015215:Zidovudine / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use
D000277:Adjuvants, Pharmaceutic; D004337:Drug Carriers; D005079:Excipients; D039821:Monoterpenes; D000431:Ethanol; D015215:Zidovudine