273. NALTREXONE ESTER PRODRUG BIOCONVERSION IN A HUMAN EPIDERMIS EQUIVALENT.

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Stinchcomb¹, A., Hammell¹, D., Challapalli¹, P., Paxton¹, E., Swaan², P., Klausner³, M., ¹University of Kentucky College of Pharmacy, Lexington, KY, ²The Ohio State University College of Pharmacy, Columbus, OH, ³MatTek Corporation, Ashland, MA. Presented at the American Association of Pharmaceutical Scientists Meeting, November (2002).

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.¹

Human skin equivalent models (EpiDerm) can be useful tools for assessing epidermal drug metabolism and topical/transdermal prodrug metabolic conversion.

The purpose of this study by scientists at the University of Kentucky College of Pharmacy, Ohio State University College of Pharmacy, and MatTek Corp. was to evaluate the transdermal naltrexone prodrugs' bioconversion rates in the EpiDerm human epidermis model.

A branched-chain (naltrexone-3-(2'-ethylbutyrate) or EtBut) and a straight-chain (naltrexone-3-valerate or VAL) prodrug were evaluated. Liquid chromatography-mass spectrometry (LC/MS) was used to quantitate prodrug, naltrexone (NTX), and 6-â-naltrexol (NTXol) levels. 6-â-naltrexol is naltrexone's major active metabolite formed after systemic administration in humans.

Conclusions:
o Metabolic conversion of the prodrugs to naltrexone and naltrexone to its active metabolite occurred in the EpiDerm human skin model.

o The straight-chain prodrug hydrolyzed at a significantly faster rate than the branched-chain prodrug (paired t-test, p<0.01).

o Human surgical waste tissue provided longer prodrug half-lives, as compared to the EpiDerm homogenates. This may be because the protein levels were higher in the EpiDerm homogenates, or because the human skin homogenates contained more dermal than epidermal tissue, or a combination of these factors.

o Use of a metabolically active human epidermal model like EpiDerm may provide a good prediction of topical/transdermal drug metabolism in the clinical setting.

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EpiDerm Data Sheet

EpiDerm Specifications

EpiDerm Technical References

Percutaneous Absorption (EpiDerm Application)

Transdermal Drug Delivery (EpiDerm Application)

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Applications: Drug absorption - skin, Drug delivery - transdermal, Metabolism - drug, Metabolism - skin, Percutaneous absorption/penetration, Transdermal permeation/penetration

Keywords: Bioconversion, Drug delivery, EpiDerm, Lipophilic alkyl ester prodrugs, Metabolism, Metabolite, Metabolize, NTxol, Naltrexol, Naltrexone, Percutaneous absorption, Permeability, Skin diffusion, Topical, Transdermal, Transdermal delivery, Transdermal drug delivery

Materials Tested: NTX, NTxol, Naltrexol, Naltrexone

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