Increase in the plasma protein binding of weakly basic drugs in carbon tetrachloride-intoxicated rats

Plasma protein binding of weakly basic drugs such as propranolol and quinidine was determined in rats with carbon tetrachloride (CCl4)-induced hepatic disease. Free fractions of propranolol and quinidine in the plasma of rats at 24 h after CCl4-intoxication were decreased by 41 and 30%, respectively, compared to those of control rats. An addition of Tris (butoxyethyl) phosphate (TBEP), a specific displacer for basic drugs from alpha 1-acid glycoprotein (AGP), to the plasma increased the free fractions of the basic drugs, resulting in no difference in the extent of the plasma free fraction of each drug between control and CCl4-intoxicated rats. Plasma concentration of AGP in CCl4-intoxicated rats was elevated 2.7-fold of that in control rats at 24 h after the CCl4 intoxication and reached a peak of 4.8-fold elevation at 48 h. A regression analysis revealed a high degree of positive correlation between ratios of bound to free fraction of propranolol and plasma concentrations of AGP. These results suggest that the plasma protein binding of the basic drugs was increased mainly due to the rise in the plasma AGP concentration in CCl4-intoxicated rats.