THE DISPOSITION OF PROPRANOLOL. IV. A DOMINANT ROLE FOR TISSUE UPTAKE IN THE DOSEDEPENDENT EXTRACTION OF PROPRANOLOL BY THE PERFUSED RAT LIVER

¹ Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee

The extraction and metabolism of propranolol durin a single, five-minute passage through the perfused rat liver has been investigated over a wide dose range from 0.05 to 4.0 mg/g of liver per 5 min. With low doses, little drug appeared in the effluent perfusate. but as the dose was increased, progressively more drug escaped elimination until the amount of drug in the effluent increased linearly with doses above 1 mg/g of liver per 5 min. Unchanged drug accumulated in the liver at all doses. Pretreatment with SKF 525A (100 mg/kg one hour before perfusion) inhibited metabolism but had little effect on the unchangd drug in the liver or on hepatic extraction. Phenobarbital (75 mg/kg day for three days) increased metabolism and had little effect on unchanged drug in the liver, but the curve for drug appearing in the effluent was shifted to the right. The hepatic/effluent drug concentration ratio decreased as the dose was increased,suggesting two uptae processes for unchanged propranolol, one with high affinity and low capacity and one with low capacity and high affinity Uptake was uhffected by SKF 525A, but the capacity of the high-affinity process was increased by phenobarbital. The rate of metabolism of the drug in the liver did not follow Michaelis-Menten kinetics with respect to total hepatic drug concentration. A kinetic model was developed, used to simulate the experimental conditions and showed good agreement when two tissue binding sites for the drug were assumed and metabolism of the resulting free drug followed Michaelis-Menten kinetics. In addition, a good fit to the SKF 525A data was obtained when only competitive drug inhibition was simulated. For phenobarbital pretreatment an adequate fit required an increased high-affinity binding capacity and an increase in V_max for metabolism. It is concluded that the complete hepatic extraction of propranolol is due to high-affinity drug uptake into the liver (probably due to tissue binding) and that the dose-hependent reduction in extraction ratio results from saturation of this high-affinity uptake process.