Physicochemical evaluation, in vitro human skin diffusion, and concurrent biotransformation of 3-O-alkyl carbonate prodrugs of naltrexone

• Published in: Pharmaceutical research 2004-07, Vol.21 (7), p.1146-1152
• Main Authors: Pillai, Omathanu, Hamad, Mohamed O, Crooks, Peter A, Stinchcomb, Audra L
• Format: Article
• Language: English
• Subjects: Biotransformation; Drug Stability; Epidermis - metabolism; Formates - chemistry; Humans; In Vitro Techniques; Molecular Weight; Naltrexone - analogs & derivatives; Naltrexone - chemistry; Naltrexone - pharmacokinetics; Narcotic Antagonists - chemistry; Narcotic Antagonists - pharmacokinetics; Permeability; Prodrugs - chemical synthesis; Prodrugs - pharmacokinetics; Skin Absorption; Solubility; Structure-Activity Relationship; Time Factors; Transition Temperature
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/B:PHAM.0000033000.03652.73

The purpose of this study was to evaluate the physicochemical properties and in vitro human skin diffusion of the 3-O-alkyl carbonate prodrugs of naltrexone (NTX). Melting points and heats of fusion (deltaHf) were determined using differential scanning calorimetry. In vitro human skin permeation rates of NTX and its prodrugs were measured using a flowthrough diffusion cell system. Drug disposition in the skin was quantified at the end of the diffusion experiment. The solubilities of the drugs were determined in mineral oil and isotonic buffer. Partitioning of the prodrugs from vehicle to skin was determined using isolated sheets of human stratum corneum (SC). All the prodrugs hydrolyzed to NTX on passing through the skin, and the methyl NTX-3-O-carbonate (ME-NTX) provided the highest NTX flux, apparent permeability coefficient (Kp), and calculated relative thermodynamic activity from the melting point and deltaHf. The ME-NTX SC/vehicle partition coefficient was the highest of the prodrug series, although similar to the NTX SC/vehicle partition coefficient value. The shortest chain prodrugs underwent the highest extent of bioconversion to NTX upon passing through the skin. Within this 3-O-alkyl carbonate prodrug series, the shortest chain prodrug was the most skin-permeable compound with the highest partition coefficient and a significant extent of bioconversion.