title: In vivo evaluation of a transdermal codrug of 6-beta-naltrexol linked to hydroxybupropion in hairless guinea pigs.
abstract: 6-Beta-naltrexol is the major active metabolite of naltrexone, NTX, a potent mu-opioid receptor antagonist used in the treatment of alcohol dependence and opioid abuse. Compared to naloxone, NTX has a longer duration of action largely attributed to 6-beta-naltrexol. This study was carried out in order to determine percutaneous absorption of a transdermal codrug of naltrexol, 6-beta-naltrexol-hydroxybupropion codrug (CB-NTXOL-BUPOH), in hairless guinea pigs as well as to evaluate the safety of 6-beta-naltrexol for development as a transdermal dosage form. This codrug may be useful in the simultaneous treatment of alcohol dependence and tobacco addiction. The carbonate codrug traversed the skin at a faster rate than 6-beta-naltrexol. 6-Beta-naltrexol equivalent steady state plasma concentrations of 6.4 ng/ml were obtained after application of the codrug as compared to 1.2 ng/ml from 6-beta-naltrexol base. The steady state plasma concentration of hydroxybupropion after codrug application was 6.9 ng/ml. Skin sensitization and irritation tested in the hairless guinea pigs using the Buehler method revealed that 6-beta-naltrexol had no skin sensitizing potential. The method was validated with a known sensitizer, p-phenylenediamine, which induced sensitization in 90% of the animals. 6-beta-Naltrexol caused only mild transient skin irritation after the initial application of the patch. During subsequent applications, erythema was slightly increased but no skin damage was observed. In conclusion, a transdermal codrug of 6-beta-naltrexol could be a viable alternative treatment for alcohol and opiate abuse.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 725 Rose Street, Lexington, KY 40536-0082, USA.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Kiptoo
authors.forename: Kalpana S
authors.initials: KS
authors.lastname: Paudel
authors.forename: Dana C
authors.initials: DC
authors.lastname: Hammell
authors.forename: Mohamed O
authors.initials: MO
authors.lastname: Hamad
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Audra L
authors.initials: AL
authors.lastname: Stinchcomb
mesh_terms: D000279:Administration, Cutaneous; D019973:Alcohol-Related Disorders / Q000188:drug therapy; D000818:Animals; D016642:Bupropion / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006168:Guinea Pigs; D008297:Male; D013058:Mass Spectrometry; D015394:Molecular Structure; D009271:Naltrexone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D012867:Skin / Q000187:drug effects; D012869:Skin Absorption / Q000187:drug effects*; D023422:Skin Irritancy Tests; D016540:Smoking Cessation / Q000379:methods
chemical_list: D011355:Prodrugs; D016642:Bupropion; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone; C496215:radafaxine