title: Disposition of d-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats.
abstract: Pharmacokinetic studies concerning d-penicillamine (an acetaldehyde sequestering agent) are scarce and have not evaluated the influence of chronic ethanol consumption and age on its disposition. Since recent preclinical studies propose d-penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors on d-penicillamine disposition in order to guide future clinical studies on the anti-relapse efficacy of this drug in alcoholism. Additionally, the effect of the administered dose was also evaluated. To this end, three studies were carried out. Study 1 assessed the influence of dose on d-penicillamine disposition, whereas studies 2 and 3 evaluated, respectively, the influence of chronic alcohol consumption and age. Rapid intravenous administrations of 2, 10 and 30 mg/kg of d-penicillamine were performed using young or adult ethanol-naïve rats or adult ethanol-experienced (subjected to a long-term ethanol self-administration protocol) rats. Pharmacokinetic parameters were derived from the biexponential model. Statistical analysis of CL, normalized AUC0 (∞) , V1 and k10 revealed that disposition, in the range plasma concentrations assayed, is non-linear both in young ethanol-naïve and in adult ethanol-experienced rats. Notably, no significant changes in t1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t1/2 . d-Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non-linear, the lack of significant alterations of the t1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d-penicillamine disposition but, again, does not modify t1/2.
authors.affiliation: Departament de Farmàcia i Tecnologia Farmacèutica, Universitat de València, Avda Vicente Andrés Estellés s/n, 46100, Burjassot, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Orrico
authors.forename: Lucía
authors.initials: L
authors.lastname: Martí-Prats
authors.forename: M José
authors.initials: MJ
authors.lastname: Cano-Cebrián
authors.forename: Ana
authors.initials: A
authors.lastname: Polache
authors.forename: Teodoro
authors.initials: T
authors.lastname: Zornoza
authors.forename: Luis
authors.initials: L
authors.lastname: Granero
mesh_terms: D000367:Age Factors; D000437:Alcoholism / Q000503:physiopathology*; D000818:Animals; D019540:Area Under Curve; D002614:Chelating Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D006207:Half-Life; D008297:Male; D017711:Nonlinear Dynamics; D010396:Penicillamine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002614:Chelating Agents; D000431:Ethanol; D010396:Penicillamine
keywords: chronic ethanol consumption; d-penicillamine; pharmacokinetics