Effect of biliary diversion on the ability of cefamandole to inhibit vitamin K metabolism.
The effect of biliary diversion on the ability of cefamandole, a methyltetrazole-thiol (MTT) containing antibiotic, to alter both hepatic vitamin K metabolism and the gamma-carboxylation of glutamic acid were examined in the rat, in order to understand the hypoprothrombinemia associated with MTT-containing antibiotics. At a dose of 3 gm/kg, cefamandole decreased the activity of hepatic vitamin K epoxide reductase at 24 but not at 4 hours after its administration. This inhibition occurred with or without diversion of the bile duct from the intestine. When vitamin K was used as the cofactor in the enzymatic reaction, carboxylation of glutamic acid was also found to be reduced in both biliary diverted as well as in biliary intact rats. Carboxylation of glutamic acid was not reduced when vitamin K hydroquinone was used. These results suggest that part of the mechanism underlying the hypoprothrombinemia associated with MTT containing antibiotics is linked to the ability of the MTT group to inhibit vitamin K metabolism. Furthermore, biliary secretion of the intact antibiotic may not be required for the effect upon vitamin K metabolism to be observed.
Tibbitts
J S
JS
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Lipsky
J J
JJ
D000818:Animals; D001652:Bile Ducts / Q000502:physiology*; D002435:Cefamandole / Q000494:pharmacology*; D003864:Depression, Chemical; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013777:Tetrazoles / Q000494:pharmacology; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases
D013777:Tetrazoles; D014812:Vitamin K; C038625:1-N-methyl-5-thiotetrazole; D002435:Cefamandole; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases