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BIOCONVERSION OF NALTREXONE AND ITS 3-O-ALKYL-ESTER PRODRUGS IN A HUMAN SKIN EQUIVALENT.
Hammell1, D.C., Stolarczyk1, E.I., Klausner2, M., Hamad1, M.O., Crooks1, P.A., Stinchcomb1, A.L.
1Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082; 2MatTek Corporation, Ashland, Massachusetts 01721.
J Pharm Sci, 94, 828–836, (2005).
Keywords: Bioconversion, ETBUT, EpiDerm 200, Epiderm 606, Epiderm 606X, HPLC, Human epidermis model, Human skin, In vitro models, In vtitro diffusion studies, Metabolism, NHEK, Naltrexol, Naltrexone (NTX), Naltrexone-3-0-Valerate, Percutaneous absorption, Permeation, Prodrug bioconversion, Prodrugs , Tissue engineering, Topical/transdermal prodrug bioconversion, Transdermal drug delivery, VAL
Endpoints: HPLC
Materials Tested: ETBUT, NTX, NTXol, VAL
Summary: The purpose of this study was to compare the percutaneous absorption and bioconversion of naltrexone (NTX), naltrexone-3-O-valerate (VAL), and naltrexone-3-O-(20-ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm™) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-b-naltrexol (NTXol) were quantitated and compared in the EpiDerm and in excised fresh human skin. VAL and ETBUT diffusion and bioconversion studies were also completed in EpiDerm. Naltrexone bioconverted to levels of 3±2% NTXol in the EpiDerm and 1±0.5% in fresh human skin. VAL hydrolyzed rapidly in the EpiDerm and mainly (93±4%) NTX was found in the receiver compartment, similar to human skin. More intact ETBUT permeated the EpiDerm tissue compared to VAL, and only 15±11%NTXwas found in the receiver. Significantly higher fluxes of NTX and the prodrugs were observed with the EpiDerm compared to human skin. A similar flux enhancement level was observed for VAL, compared to NTX base, in the EpiDerm and the human skin. Metabolically active human epidermal models like EpiDerm are useful as an alternative experimental system to human skin for prediction of topical/transdermal drug/prodrug bioconversion.
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Percutaneous Absorption (EpiDerm Application)
Transdermal Drug Delivery (EpiDerm Application)
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