The Influence of Increased Plasma Protein Binding on the Disposition of Quinidine in Turpentine-Treated Rats

Abstract

The effect of the increased plasma protein binding of quinidine on its disposition was investigated in turpentine-treated rats, since turpentine treatment is known to increase the plasma concentration of α₁-acid glycoprotein which preferentially binds basic drugs. The plasma free fraction of quinidine 16 and 48h after turpentine treatment was decreased by 30 and 76%, respectively, compared to the control value. The treatment did not cause liver injury nor alter the hepatic blood flow. The disappearance of quinidine in plasma after an intravenous injection (3.0, 7.0, 12.5mg/kg) was analyzed by a two-compartment open model in both control and turpentine-treated rats. The blood total body clearance (CL_b) of quinidine at 48h after the treatment was decreased by 30 to 65% in a dose-dependent manner, compared to that in control rats. The distribution volume (V_dss) of quinidine (12.5mg/kg) at 16 and 48h after turpentine treatment was decreased by 30 and 79%, respectively.Hepatic extraction ratio (HER) of quinidine, which was determined at steady state blood concentrations from 0.5 to 2.3μg/ml, was decreased from 0.8 to 0.35 with an increase in the quinidine concentration in control rats. The HER value 48h after turpentine treatment was consistently reduced by 15 to 40% in a concentration-dependent manner compared to the corresponding control value. These findings indicate that the increased plasma binding of quinidine caused a reduction of HER of the drug, and the reduced HER resulted in the decrease in CL_b in turpentine-treated rats.Tissue-to-plasma partition coefficient (K_p) for the lung, kidney, spleen, liver and heart, which was determined at a steady state plasma concentration (1μg/ml), was decreased after the turpentine treatment to the same extent as the decrease in V_dss (16h, 28-39%; 48h, 76-81%). The K_p value in each tissue was proportional to the free fraction of quinidine in the plasma. These results indicate that V_dss and K_p were reduced due to the increase in the plasma protein binding of quinidine in turpentine-treated rats.