In Vitro/in Vivo Correlation of Transdermal Naltrexone Prodrugs in Hairless Guinea Pigs

Abstract

The purpose of this investigation was to evaluate the in vitro and in vivo percutaneous absorption of the following prodrugs of naltrexone (NTX): 2'-ethylbutyryl-3-O-ester-NTX (ETBUT-ester), methyl-3-O-carbonate-NTX (ME-carbonate), ethyl-3-O-carbamate-NTX (ET-carbamate), and N,N-dimethyl-3-O-carbamate-NTX (DME-carbamate) in hairless guinea pigs. In vitro fluxes of NTX and its prodrugs through guinea pig skin were determined using a flow-through diffusion cell system. The pharmacokinetics of NTX prodrugs were determined after topical application of transdermal patches in guinea pigs. All the prodrugs hydrolyzed to NTX on passing through the skin, and ME-carbonate provided the highest NTX flux and had the highest apparent permeability coefficient (K(p)). ME-carbonate and ET-carbamate underwent the highest extent of bioconversion to NTX upon passing through the skin as compared to ETBUT-ester and DME-carbamate. The results of the in vivo studies indicated that a significant amount of NTX was delivered after the application of transdermal patches of NTX prodrugs. A mean steady-state plasma concentration of 7.1 ng/ml was obtained after the application of transdermal patches of ME-carbonate. A good correlation was obtained between the in vitro and in vivo results. The results of the in vivo studies indicated that the ME-carbonate prodrug of NTX was the most promising drug candidate for transdermal delivery.