PHARMACOLOGY OF ANTIBIOTIC-RELATED HYPOPROTHROMBINEMIA

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Several commonly used beta lactam antibiotics including cefamandole, cefoperazone, and moxalactam, have been associated with the development of hypoprothrombinemia, a side effect which may lead to serious bleeding. The research proposed here will examine the hypothesis that the hypoprothrombinemia associated with these antibiotics is a consequence of the pharmacologic activity of a common structural feature of the antibiotics, the 1-methyl-5-thiotetrazole (MTT) side group. This MTT group has been shown to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma carboxylation of glutamic acid in a rat liver microsomal system. Further in vitro analysis of the mechanism of this inhibition is proposed. Also the further metabolism of MTT as well as the ability of different thiol side groups in other beta lactam antibiotics to inhibit the carboxylation system will be investigated. An examination of the behavior in this system of drugs associated with hypoprothrombinemia such as thiourea antithyroid drugs and disulfiram will be made. In vivo experiments will be conducted in rats to further define the mechanism by which beta lactam antibiotics, thiol groups, and thiourea drugs produce hypoprothrombinemia. Not all patients on MTT-containing antibiotics develop hypoprothrombinemia; therefore the animal model will be used to identify and evaluate potential risk factors which may predispose patients to hypoprothrombinemia. For example, the effects on blood clotting due to altering the glutathione status of the animal, as well as variations in the dietary levels of vitamin K, will be examined. From the results of the proposed in vitro analysis of the MTT-induced inhibition of clotting factor synthesis, and from the results of risk factor determination in an animal model, it may be possible to predict the relative risk of hypoprothrombinemia with a given antibiotic in a given patient. Such an understanding will lead to the safer use of beta lactam antibiotics and explain the hypoprothrombinemia associated with these and related drugs.