ABSTRACTPharmacokinetic studies concerningd‐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 proposed‐penicillamine as a promising treatment for alcohol relapse, the main aim of the present work was to evaluate the influence of these two factors ond‐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 ond‐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 ofd‐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 ofCL, normalizedAUC0∞,V1andk10revealed 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 int1/2were detected. Chronic ethanol consumption significantly reducedCLvalues by 35% without affectingt1/2.d‐Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non‐linear, the lack of significant alterations of thet1/2would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also altersd‐penicillamine disposition but, again, does not modifyt1/2. Copyright © 2014 John Wiley & Sons, Ltd.