Disposition of d‐penicillamine,a promising drug for preventing alcohol‐relapse. Influence of dose,chronic alcohol consumption and age: studies in rats

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 t_1/2 were detected. Chronic ethanol consumption significantly reduced CL values by 35% without affecting t_1/2. 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 t_1/2 would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters d ‐penicillamine disposition but, again, does not modify t_1/2. Copyright © 2014 John Wiley & Sons, Ltd.