Lipsky J J, Gallego M O
Department of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Drug Metabol Drug Interact. 1988;6(3-4):317-26. doi: 10.1515/dmdi.1988.6.3-4.317.
The thioamide class of antithyroid drugs has been associated with the development of hypoprothrombinemia. Two drugs in this class, propylthiouracil and methimazole, resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics. Both were found in vitro to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid with 50 per cent inhibitory concentrations of 2 mM for propylthiouracil and 0.1 mM for methimazole. Methimazole was also found to inhibit vitamin K epoxide reductase, an enzyme related to the carboxylation reaction, with a 50 per cent inhibitory concentration of 25 uM. In vivo methimazole, administered twice at a dose of 500 mg/kg to rats on a vitamin K deficient diet produced hypoprothrombinemia. These results suggest that the mechanism of hypoprothrombinemia associated with thioamide antithyroid drugs may be similar to the mechanism of hypoprothrombinemia associated with cephalosporins which contain the methyltetrazole-thiol leaving group.
硫代酰胺类抗甲状腺药物与低凝血酶原血症的发生有关。该类中的两种药物，丙硫氧嘧啶和甲巯咪唑，类似于某些头孢菌素抗生素的甲基四氮唑-硫醇离去基团。在体外研究中发现，二者均可抑制凝血因子合成中维生素K依赖的步骤，即谷氨酸的γ-羧化反应，丙硫氧嘧啶的50%抑制浓度为2 mM，甲巯咪唑为0.1 mM。还发现甲巯咪唑可抑制维生素K环氧化物还原酶，这是一种与羧化反应相关的酶，其50%抑制浓度为25 μM。在体内实验中，给维生素K缺乏饮食的大鼠以500 mg/kg的剂量两次注射甲巯咪唑后，出现了低凝血酶原血症。这些结果表明，硫代酰胺类抗甲状腺药物所致低凝血酶原血症的机制可能与含有甲基四氮唑-硫醇离去基团的头孢菌素所致低凝血酶原血症的机制相似。
