Inhibition of vitamin K-dependent carboxylase in vitro by cefamandole and its structural analogs.
Clinical use of the beta-lactam cephalosporins has resulted in a number of reports of vitamin K-responsive bleeding abnormalities. The effects of these antibiotics on the activities of vitamin K-dependent enzymes in vitro were therefore assessed. The activity of vitamin K-dependent carboxylase was inhibited by 50% by 6-10 mM cefamandole or structurally analogous cephalosporins. The inhibition was noncompetitive with respect to the pentapeptide substrate, vitamin KH2, and CO2. Vitamin K epoxide reductase was less sensitive to and only partially inhibited by cefamandole and the analogs. The possible physiologic significance of the inhibition of these enzymes in clinical hemorrhagic problems was considered.
D000818:Animals; D019735:Carbon-Carbon Ligases; D002435:Cefamandole / Q000031:analogs & derivatives / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008025:Ligases / Q000037:antagonists & inhibitors*; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D009842:Oligopeptides / Q000378:metabolism; D011732:Pyridoxal Phosphate / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D064417:Vitamin K Epoxide Reductases
D002511:Cephalosporins; D009842:Oligopeptides; D002435:Cefamandole; D011732:Pyridoxal Phosphate; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; D008025:Ligases; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase