Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent

✍ Scribed by Dana C. Hammell; Elzbieta I. Stolarczyk; Mitch Klausner; Mohamed O. Hamad; Peter A. Crooks; Audra L. Stinchcomb

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 173 KB
• Volume: 94
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20238

✦ Synopsis

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 0 -ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm TM ) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-b-naltrexol (NTXol) were quantitated and compared in the EpiDerm TM and in excised fresh human skin. VAL and ETBUT diffusion and bioconversion studies were also completed in EpiDerm TM . Naltrexone bioconverted to levels of 3 AE 2% NTXol in the EpiDerm TM and 1 AE 0.5% in fresh human skin. VAL hydrolyzed rapidly in the EpiDerm TM and mainly (93 AE 4%) NTX was found in the receiver compartment, similar to human skin. More intact ETBUT permeated the EpiDerm TM tissue compared to VAL, and only 15 AE 11% NTX was found in the receiver. Significantly higher fluxes of NTX and the prodrugs were observed with the EpiDerm TM compared to human skin. A similar flux enhancement level was observed for VAL, compared to NTX base, in the EpiDerm TM and the human skin. Metabolically active human epidermal models like EpiDerm TM are useful as an alternative experimental system to human skin for prediction of topical/transdermal drug/prodrug bioconversion.