Bioconversion of Naltrexone and Its 3-O-Alkyl-Ester Prodrugs in a Human Skin Equivalent

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-(2′-ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm™) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-β-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% NTX was 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.