Investigation of Carbamathione Pharmacokinetics and Pharmacodynamics by In Vivo Microdialysis and Capillary Electrophoresis

Abstract

The pharmacological basis for the use of the drug disulfiram for alcoholism is its inhibition of liver aldehyde dehydrogenase (ALDH2). Recent studies have reported that disulfiram exhibited an anti-craving effect with both alcohol addiction and cocaine dependence. Inhibition of ALDH2 cannot explain disulfiram's efficacy in cocaine dependence. The disulfiram metabolite S-(N, N-diethylcarbamoyl) glutathione (carbamathione) is formed from disulfiram and appears in the brain after the administration of disulfiram. Carbamathione has no effect on liver ALDH2 and is a partial non-competitive inhibitor of the N-methyl-D-aspartic acid (NMDA) glutamate receptor. The effect of carbamathione on the neurotransmitter systems involved in craving and addiction is unknown. The aim of this research project was to develop analytical methods to determine carbamathione and relevant neurotransmitters in rat brain microdialysis samples in order to elucidate the pharmacokinetics and pharmacodynamics of carbamathione. The effect of disulfiram on the brain neurotransmitters was evaluated. The significance of this research is that carbamathione may be involved in the anti-craving effect observed with disulfiram, and thus may be used as a pharmacological tool to improve the effectiveness of disulfiram therapy in cocaine and alcohol addiction.