Effects of beta-lactam antibiotics and N-methyltetrazolethiol on the alcohol-metabolizing system in rats.
The disulfiram-like effect of various beta-lactam antibiotics containing N-methyltetrazolethiol (NMTT) on the alcohol-metabolizing system was studied using rats. Their administration caused decreased activities in low Km aldehyde dehydrogenase (ALDH) and acetaldehyde oxidation in the liver, with marked depression from several hours to 2 days after the treatment. Blood acetaldehyde level increased markedly when ethanol was administered 18-24 hr after pretreatment with antibiotics. A similar time course change in the effect was obtained when disulfiram was administered. The following results obtained in the present study indicate that the disulfiram-like effect associated with these antibiotics was not mediated by the whole molecular structures of these drugs: Firstly, the antibiotics were eliminated rapidly from the plasma and liver, and the disulfiram-like effect was followed by a disappearance of the drugs. Secondly, the concentration of antibiotics required to inhibit mitochondrial low Km ALDH activity in vitro was very high compared with their liver concentration. Thirdly, rapid onset of disulfiram-like effects occurred after administration of NMTT itself, and a pronounced elevation of blood acetaldehyde level was observed when ethanol was administered 3-5 hr after the NMTT injection. Fourthly, almost the same amounts of NMTT were released in the body after the intravenous administration of various NMTT-containing antibiotics, as judged by the urinary excretion. These results suggest that the disulfiram-like effect of beta-lactam antibiotics is mediated by NMTT released from them.
D000079:Acetaldehyde / Q000097:blood; D000438:Alcohols / Q000378:metabolism*; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000652:urine; D001393:Azoles / Q000494:pharmacology*; D002435:Cefamandole / Q000494:pharmacology; D000431:Ethanol / Q000097:blood; D006634:Histamine H1 Antagonists / Q000494:pharmacology* / Q000652:urine; D008099:Liver / Q000201:enzymology; D008297:Male; D008930:Mitochondria, Liver / Q000201:enzymology; D009070:Moxalactam / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000201:enzymology; D013777:Tetrazoles / Q000494:pharmacology* / Q000652:urine; D013997:Time Factors
D000438:Alcohols; D000900:Anti-Bacterial Agents; D001393:Azoles; D006634:Histamine H1 Antagonists; D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; D000431:Ethanol; D002435:Cefamandole; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D009070:Moxalactam