313.

NALTREXONE AND NALTREXONE-3-O-VALERATE DIFFUSION AND BIOCONVERSION IN A HUMAN EPIDERMIS EQUIVALENT. 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. Poster presented at the American Association of Pharmaceutical Scientists (AAPS), Salt Lake City, UT, October 26-30, (2003).

Keywords: Alcoholism, Bioconversion, Delivery rate, Diffusion cells, EpiDerm, EpiDerm 606 , EpiDerm 606-X, Epidermal drug metabolism, In Vitro, Metabolic conversion, Metabolism, Metabolite, Naltrexol, Naltrexone, Naltrexone-3-0-Valerate, Narcotic, Permeation, Prodrug bioconversion, Skin diffusion studies, Topical/transdermal prodrug metabolic conversion, Transdermal, Transdermal naltrexone delivery

Endpoints: Flux, HPLC, Penetration rate

Materials Tested: 6-b-naltrexol (NTXol), NTX, Naltrexone, Naltrexone-3-O-Valerate

Summary: 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.

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