Serum protein binding of phenytoin, diazepam and propranolol in chronic renal diseases

The effect of chronic renal disease on the serum free fraction of phenytoin, diazepam and propranolol was examined in vitro among 60 conservatively treated patients with renal insufficiency of varying degree and different etiology, and in 10 patients with a nephrotic syndrome. The control group comprised 10 age and sex-matched healthy subjects. The free fractions were separated at 37 degrees C using a pressure ultrafiltration method. The highest free fractions of phenytoin and diazepam in uremic patients were 4 to 5-fold the normal. The free fractions were about twice the normal at a creatinine concentration of 800 mumol/l, and 2 to 4-fold at an urea concentration of 20-40 mmol/l. The creatinine and urea correlated with the free fractions of phenytoin and diazepam in a similar manner. The effect of a decreased serum albumin on the free fractions of these drugs was clear when its concentration was under 30 g/l. The creatinine and urea did not correlate with the free fraction of propranolol. However, after mathematically correcting the free fraction of propranolol to correspond to an alpha 1-acid glycoprotein (alpha 1-AGP) concentration of 0.9 g/l, it correlated significantly with creatinine and urea. The concentration of alpha 1-AGP was the most important determinant for the free fraction of propranolol. For practical purposes, the change in the free fractions of phenytoin and diazepam can be adequately predicted by the serum creatinine or urea and serum albumin levels. For propranolol the only parameter which needs to be analyzed is the serum alpha 1-AGP concentration.