NALTREXONE AND NALTREXONE-3-O-VALERATE DIFFUSION AND BIOCONVERSION IN A HUMAN EPIDERMIS EQUIVALENT.

• TR Number: 313
• Authors: Stinchcomb1, A.L., Hammell1, D.C., Stolarczyk1, E.I., Klausner2, M., Hamad1, M., Crooks1, P.A. 1Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, 2Mattek Corporation, Ashland, MA.
• Materials Tested: 6-b-naltrexol (NTXol), NTX, Naltrexone, Naltrexone-3-O-Valerate

Transdermal naltrexone delivery may help improve patient compliance in the treatment of narcotic dependence and alcoholism. Lipophilic alkyl ester prodrugs increase the delivery rate of naltrexone across human surgical waste skin in vitro. Human skin equivalent models can be useful tools for assessing epidermal drug metabolism and topical/transdermal prodrug metabolic conversion. The purpose of this study was to evaluate the transdermal naltrexone prodrugs’ bioconversion and diffusion in a human epidermis model. A straight-chain (naltrexone-3-O-valerate or VAL) and a branched-chain (naltrexone-3-O-(2′-ethylbutyrate) or EtBut) prodrug were evaluated, along with naltrexone base (NTX). Prodrug bioconversion to NTX, and NTX conversion to 6-b-naltrexol (NTXol) were measured in the human skin equivalents (EpiDerm™ 606 and 606X). 6-b-naltrexol is naltrexone’s major active metabolite formed after systemic administration in humans.