Disposition of d‐penicillamine, a promising drug for preventing alcohol‐relapse. Influence of dose, chronic alcohol consumption and age: studies in rats. (6th April 2014)

• Record Type: Journal Article
• Authors: Orrico, Alejandro; Martí‐Prats, Lucía; Cano‐Cebrián, M. José; Polache, Ana; Zornoza, Teodoro; Granero, Luis
• Is Part Of: Biopharmaceutics & drug disposition. Volume 35:Number 5(2014:Jul.)
• Page Start: 284
• Page End: 295
• Publication Date: 2014-04-06
• Subjects: Biopharmaceutics -- Periodicals; Drugs -- Metabolism -- Periodicals; Pharmacology -- Periodicals; Biopharmaceutics -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; 615.19
• DOI: 10.1002/bdd.1896
• Languages: English
• ISSNs: 0142-2782

Abstract

<abstract abstract-type="main"> <title>ABSTRACT</title> <p>Pharmacokinetic studies concerning <sc>d</sc>‐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 <sc>d</sc>‐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 <sc>d</sc>‐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 <sc>d</sc>‐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 <sc>d</sc>‐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 <italic>CL</italic>, normalized <italic>AUC</italic><sub>0</sub><sup>∞</sup>, <italic>V</italic><sub>1</sub> and <italic>k</italic><sub>10</sub> 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 <italic>t</italic><sub>1/2</sub> were detected. Chronic ethanol consumption significantly reduced <italic>CL</italic> values by 35% without affecting <italic>t</italic><sub>1/2</sub>. <sc>d</sc>‐Penicillamine disposition was equivalent in young and adult animals. In conclusion, although DP pharmacokinetics is non‐linear, the lack of significant alterations of the <italic>t</italic><sub>1/2</sub> would potentially simplify the clinical use of this drug. Chronic consumption of ethanol also alters <sc>d</sc>‐penicillamine disposition but, again, does not modify <italic>t</italic><sub>1/2</sub>. Copyright © 2014 John Wiley & Sons, Ltd.</p> </abstract>