Pharmacokinetics of latamoxef and N-methyltetrazolethiol in rats associated with the development of disulfiram-like effects.
The disulfiram-like effect of beta-lactam antibiotics, having an N-methyltetrazolethiol (NMTT) as a 3'-position substituent of the cephalosporin nucleus, was determined in rats using latamoxef (LMOX) as a model. Intravenous and subcutaneous administrations of these antibiotics caused a decrease in the low Km aldehyde dehydrogenase (ALDH) activity in liver mitochondria and an increase in blood acetaldehyde level during ethanol metabolism, as in the case of disulfiram. When the antibiotic was administered intravenously to biliary fistula rats, the blood acetaldehyde level did not increase. On the other hand, oral administration of antibiotic to normal and biliary fistula rats caused pronounced development of disulfiram-like effects in both animals. When LMOX was injected to normal rats, the rapid and slow eliminations of LMOX and NMTT, respectively, were observed from blood and liver. After oral administration of LMOX, NMTT remained in the blood and liver for a long time with higher concentrations, although LMOX could not be detected in the body. With biliary fistula rats, intravenous injection of LMOX led to rapid urinary excretion of both LMOX and NMTT. These results indicate that the development of disulfiram-like effects of NMTT-containing antibiotics is closely related to the pharmacokinetic profile of NMTT released from its parent drugs.
Shionogi Research Laboratories, Shionogi & Co. Ltd., Osaka, Japan.
T
T
Matsubara
S
S
Otsubo
A
A
Ogawa
T
T
Oka
D000079:Acetaldehyde / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D001393:Azoles / Q000493:pharmacokinetics*; D001646:Bile / Q000378:metabolism; D004221:Disulfiram / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D009070:Moxalactam / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000493:pharmacokinetics* / Q000494:pharmacology
D001393:Azoles; D013777:Tetrazoles; C038625:1-N-methyl-5-thiotetrazole; D000431:Ethanol; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D004221:Disulfiram; D009070:Moxalactam