Disulfiram. methylation

The answer is a. (Hardman, pp 1086—1089.) Intolerance of alcohol (disulfiram-like reaction) has been noted only with certain cephalosporins. Cephalosporins with the methylthiotetrazole side chain have been associated with a disulfi ram-like reaction because the methyl thiotetrazole group has a configuration similar to disulfi ram, which blocks the metabolism of alcohol at the acetaldehyde step. Accumulation of acetaldehyde is associated with the symptoms. The methyl thiotetrazole side chain also results in hypopro thrombi nemia by interfering with the synthesis of vitamin K-dependent clotting factors. 

The adverse effects associated with cefazolin are generally similar to those described for penicillins. Cefazolin contains a methylthiodiazolethiol side chain and may further cause hypoprothrombinemia and a disulfiram-like reaction with alcohol similar to that seen witli cephalosporins containing the related A-methyl-thiotetrazole side chain. 

Thiol S-methyltransferase is a microsomal enzyme found in the liver, lung, and kidney, which will catalyze the methylation of a wide variety of foreign compounds. A number of sulfur-containing drugs such as disulfiram, D-penicillamine, and 6-mercaptopurine are methylated in humans by thiol S-methyltransferase or thiopurine methyltransferase. Methylation of the anticancer drug thiopurine by the latter enzyme is a detoxication reaction, reducing the myelotoxicity of the drug (see Fig. 4.18, which shows the reverse of this reaction). 

Madan A, Parkinson A, Faiman MD. Identification of the human and rat P450 enzymes responsible for the sulfoxidation of S-methyl N,N-diethylthiolcarhamate (DETC-ME). The terminal step in the bioactivation of disulfiram. Dmg Metab Dispos 1995 23 1153-1163. 

Following a single oral dose of 250 mg to 15 subjects, mean peak plasma concentrations of 0.38 pg/ml of disulfiram, 0.77 pg/ml of diethyldithiocarbamic acid, 0.30 pg/ml of methyl diethyldithiocarbamate, and 1.7 pg/ml of diethylamine were attained in about 9 hours a mean peak plasma concentration of 22 pg/ml of carbon disulphide was reported at 6 hours there was considerable intersubject variability in the plasma concentrations (M. D. Faiman etai, Clin. Pharmac. Ther., 1984, 36, 520-526). 

Swenberg JA, Cooper HK, Bucheler J, et al. 1979. 1,2-Dimethylhydrazine-induced methylation of DNA bases in various rat organs and the effect of pretreatment with disulfiram. Cancer Res 39 465-467. 

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