Mechanism of thioamide antithyroid drug associated hypoprothrombinemia.
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.
Lipsky
J J
JJ
Department of Medicine and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Gallego
M O
MO
D000577:Amides / Q000633:toxicity*; D000818:Animals; D013956:Antithyroid Agents / Q000633:toxicity*; D005971:Glutamates / Q000378:metabolism; D007020:Hypoprothrombinemias / Q000139:chemically induced* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008713:Methimazole / Q000633:toxicity; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D011441:Propylthiouracil / Q000633:toxicity; D011517:Prothrombin Time; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000633:toxicity*; D064417:Vitamin K Epoxide Reductases
D000577:Amides; D013956:Antithyroid Agents; D005971:Glutamates; D013854:Thioamides; D008713:Methimazole; D011441:Propylthiouracil; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases