Distribution of quinidine in rats with carbon tetrachloride-intoxicated hepatic disease

The disposition of quinidine was investigated in rats with experimental hepatic disease caused by an intraperitoneal injection of CCl4. The plasma disappearance of quinidine after a 12.5 mg/kg i.v. bolus injection was analyzed by a two-compartment open model in both control and CCl4-intoxicated rats. In the CCl4-intoxicated rats, plasma total body clearance (CLtot), elimination rate constant of the central compartment (kel) and the volume of distribution (Vdss) of quinidine were decreased by 73, 51 and 36%, respectively, compared to those in the control rats. At a steady state of quinidine plasma concentration of 1 micrograms/ml, tissue-to-plasma partition coefficient (Kp,vivo) of the drug in the lung, spleen, heart, kidney and liver in the CCl4-intoxicated rats were decreased ranging from 32 to 42% compared to those in the control rats. The plasma free fraction of quinidine in the intoxicated rats was decreased by 34% of that in the control rats. Neither tissue binding of quinidien in vitro, nor plasma pH was altered in the intoxicated rats. Thus, the decrease in Vdss and Kp,vivo for quinidine in the intoxicated rats seems likely to be due to an increase in plasma protein binding of the drug. Metabolic activity in the liver, the hepatic extraction ratio for quinidine, and the hepatic blood flow in the CCl4-intoxicated rats were decreased by 84, 57 and 47%, respectively, compared to those in the control rats. The decrease in CLtot and kel in the intoxicated rats is considered to be attributed to both the reduction of liver functions and the increase in the plasma protein binding of the drug.