Production of hypoprothrombinaemia by cefazolin and 2-methyl-1,3,4-thiadiazole-5-thiol in the rat.
Recent findings have suggested that the 1-methyltetrazole-5-thiol (MTT) group contained in several beta-lactam antibiotics may be responsible for the hypoprothrombinaemia associated with these drugs. In order to determine if the hypoprothrombinaemia associated with cefazolin is due to the presence of the structurally related 2-methyl-1,3,4,-thiadiazole-5-thiol (MTD) group which it possesses, the ability of MTD and cefazolin to produce hypoprothrombinaemia in rats was examined. Female rats maintained on a vitamin K-deficient diet for ten days developed hypoprothrombinaemia after the intravenous administration of cefazolin for two subsequent days. Hypoprothrombinaemia was also produced by the oral administration to vitamin K-deficient rats of either cefazolin or MTD, while the oral administration of cefotaxime, which does not contain a thiol group, had no effect. In a rat liver microsomal system, MTD was found to be a much more potent inhibitor than cefazolin of the vitamin K-dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid. These results suggest that the hypoprothrombinaemia associated with cefazolin may be due to the MTD group.
D000284:Administration, Oral; D000818:Animals; D002437:Cefazolin / Q000008:administration & dosage / Q000633:toxicity*; D002439:Cefotaxime / Q000633:toxicity; D005260:Female; D005971:Glutamates / Q000378:metabolism; D018698:Glutamic Acid; D007020:Hypoprothrombinemias / Q000139:chemically induced*; D008862:Microsomes, Liver / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013830:Thiadiazoles / Q000633:toxicity*; D014813:Vitamin K Deficiency
D005971:Glutamates; D013830:Thiadiazoles; C049131:2-methyl-1,3,4-thiadiazole-5-thiol; D018698:Glutamic Acid; D002437:Cefazolin; D002439:Cefotaxime