Serum protein binding of drugs during and after pregnancy in rats

The serum protein binding of salicylic acid (SA), sulfisoxazole (SUL), phenytoin (P), dexamethasone (D), diazepam (DI) and bilirubin (B) was determined in Long-Evans rats during pregnancy and after parturition. Serum free fraction (f) values were obtained by equilibrium dialysis (drugs) and by a reaction rate method (B). Concurrent control experiments were carried out on nonpregnant animals. Values of f were not significantly different from controls during the first 10 to 15 days of pregnancy. Pronounced increases in f of SA, SUL, P and D were observed on the 20th and 21st day of pregnancy; the f of DI was increased only on the 21st day and the f of B was not significantly changed at any time. The f values for SA, SUL and P returned almost to control levels 2 days after parturition (D, DI and B were not studied at that time). Additional studies with SUL, P and D on the 20th day of pregnancy showed that the increase in f occurred over a wide concentration range. Total serum protein and albumin concentrations were significantly decreased only on the 21st day of pregnancy. Pretreatment with activated charcoal decreased f of SA, SUL, P and D (the other compounds were not studied) in serum of 20-day pregnant (but not control) animals. The decreased protein binding of drugs in serum of pregnant rats appears to be due, at least in part, to accumulation of endogenous displacing agents.