Disposition of d-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats
Version of Record online: 6 APR 2014
Copyright © 2014 John Wiley & Sons, Ltd.
Biopharmaceutics & Drug Disposition
Volume 35, Issue 5, pages 284–295, July 2014
How to Cite
Orrico, A., Martí-Prats, L., Cano-Cebrián, M. J., Polache, A., Zornoza, T. and Granero, L. (2014), Disposition of d-penicillamine, a promising drug for preventing alcohol-relapse. Influence of dose, chronic alcohol consumption and age: studies in rats. Biopharm. Drug Dispos., 35: 284–295. doi: 10.1002/bdd.1896
- Issue online: 3 JUL 2014
- Version of Record online: 6 APR 2014
- Accepted manuscript online: 12 MAR 2014 02:41AM EST
- Manuscript Accepted: 9 MAR 2014
- Manuscript Revised: 20 JAN 2014
- Manuscript Received: 31 OCT 2013
- chronic ethanol consumption
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. Copyright © 2014 John Wiley & Sons, Ltd.