Plasma protein binding of metbufen, a new non-steroid anti-inflammatory drug, in humans

The binding of 14C-metbufen to human serum albumin and to plasma of cirrhotic patients was measured by equilibrium dialysis at 37 degrees C, pH = 7.4. Between 0.37-373 microM, binding of metbufen to human serum is linear and 99% complete. HSA is the only binding protein with two classes of saturable binding sites. The binding parameters are n1 = 3-5; K1 = 40000 M-1; n2 = 5-8; K2 = 2000 M-1 and n1 = 2; K1 = 148000 M-1, n2 = 7.5; K2 = 2800 M-1 to serum (600 microM HSA) and HSA (600 microM), respectively. The higher affinity constants of pure commercial HSA than found in serum and the lower number of binding sites are thought to be due to albumin polymerization in commercial HSA. In plasma from cirrhotic patients (total bilirubin: 232 microM; HSA = 450 microM), at 7.5 and 30 microM, metbufen-free fractions increased from 1.4 to 2.4% and 1.3 to 3.6%, respectively. At 2 or 8 micrograms/ml, metbufen is not displaced by salicylic acid (300 micrograms/ml), CPIB (200 micrograms/ml), furosemide (2 micrograms/ml), itanoxone (20 micrograms/ml), tolbutamide (100 micrograms/ml), warfarin (3 micrograms/ml), or diazepam (0.75 micrograms/ml). Finally, metbufen interacts with both the diazepam and warfarin binding sites of HSA to some degree.