Abstract

The disulfiram-ethanol-reaction (DER) will be studied in rats in order to correlate the pharmacokinetic aspects of disulfiram and its metabolites diethyldithiocarbamate and diethyldithiocarbamate-methyl ester with the pharmacodynamics of the DER. Biochemical parameters to be measured include plasma disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, CS2 and diethylamine. Blood ethanol and acetaldehyde as well as brain and liver aldehyde dehydrogenase (low and high Km) in mitochondrial, lysomal, microsomal and supernatant fractions will be determined. Physiological measurements will include heart rate, blood pressure, and core temperature. Using drugs as pharmacological tools, the role of aldehyde dehydrogenase, dopamine-Beta-hydroxylase, acetaldehyde, and ethanol in the DER will be evaluated. Ascorbate-protein binding interactions in vivo in rats, its effect on negating the DER, and the correlation with the various biochemical and physiological parameters will be studied. The pharmacodynamics of the DER also will be investigated to delineate the role of brain dopamine and norepinephrine receptors. Included are studies employing the central administration of 6-hydroxydopamine, a catecholamine neurotoxin, to study the interaction between disulfiram and ethanol in producing the DER.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA003577-07
Application #
3108846
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1984-09-01
Project End
1991-06-30
Budget Start
1987-09-01
Budget End
1991-06-30
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Kansas Lawrence
Department
Type
Schools of Pharmacy
DUNS #
072933393
City
Lawrence
State
KS
Country
United States
Zip Code
66045

  Publications

Madan, A; Parkinson, A; Faiman, M D (1998) Identification of the human P-450 enzymes responsible for the sulfoxidation and thiono-oxidation of diethyldithiocarbamate methyl ester: role of P-450 enzymes in disulfiram bioactivation. Alcohol Clin Exp Res 22:1212-9
Hart, B W; Faiman, M D (1995) Inhibition of rat liver low Km aldehyde dehydrogenase by thiocarbamate herbicides. Occupational implications. Biochem Pharmacol 49:157-63
Madan, A; Parkinson, A; Faiman, M D (1995) Identification of the human and rat P450 enzymes responsible for the sulfoxidation of S-methyl N,N-diethylthiolcarbamate (DETC-ME). The terminal step in the bioactivation of disulfiram. Drug Metab Dispos 23:1153-62
Madan, A; Faiman, M D (1995) Characterization of diethyldithiocarbamate methyl ester sulfine as an intermediate in the bioactivation of disulfiram. J Pharmacol Exp Ther 272:775-80
Madan, A; Williams, T D; Faiman, M D (1994) Glutathione- and glutathione-S-transferase-dependent oxidative desulfuration of the thione xenobiotic diethyldithiocarbamate methyl ester. Mol Pharmacol 46:1217-25
Madan, A; Faiman, M D (1994) NADPH-dependent, regioselective S-oxidation of a thionosulfur- and thioether-containing xenobiotic, diethyldithiocarbamate methyl ester by rat liver microsomes. Drug Metab Dispos 22:324-30
Nagendra, S N; Madan, A; Faiman, M D (1994) S-methyl N,N-diethylthiolcarbamate sulfone, an in vitro and in vivo inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase. Biochem Pharmacol 47:1465-7
Hart, B W; Faiman, M D (1994) In vivo pharmacodynamic studies of the disulfiram metabolite S-methyl N,N-diethylthiolcarbamate sulfoxide: inhibition of liver aldehyde dehydrogenase. Alcohol Clin Exp Res 18:340-5
Madan, A; Faiman, M D (1994) Diethyldithiocarbamate methyl ester sulfoxide, an inhibitor of rat liver mitochondrial low Km aldehyde dehydrogenase and putative metabolite of disulfiram. Alcohol Clin Exp Res 18:1013-7
Madan, A; Parkinson, A; Faiman, M D (1993) Role of flavin-dependent monooxygenases and cytochrome P450 enzymes in the sulfoxidation of S-methyl N,N-diethylthiolcarbamate. Biochem Pharmacol 46:2291-7

Showing the most recent 10 out of 18 publications