Effect of age on the hepatic clearance of propranolol in rats

Abstract

The effect of age on hepatic clearance of propranolol was investigated in male Wistar rats (3 to 104 weeks old). Pharmacokinetic analysis of the plasma propranolol data obtained after i.v. dosage (1.0 mg kg-1) indicated that both the elimination rate constant and the volume of distribution decreased with age between weeks 5 and 11, after when the distribution volume remained almost constant. The elimination rate constant was reduced consistently with age after 15 weeks. Total body clearance of the drug was reduced extensively with age between weeks 5 and 11 (94 to 43 ml min-1 kg-1) and decreased gradually thereafter. The plasma free fraction of propranolol also decreased with age, falling from more than 20% in 3 to 5 weeks-old rats to about 10% in rats of 52 to 104 weeks. In immature rats the renal clearance was approximately 5 to 12% of the total body clearance. Intrinsic hepatic clearance for unbound propranolol also decreased with age between weeks 7 and 24. As expected from the evidence that propranolol has a high extraction ratio, the extent of its hepatic clearance was significantly dependent on the liver blood flow. These data suggest that the age-dependent decrease in hepatic clearance of propranolol is largely due to a reduction of the elimination rate that might be accompanied by the age-dependent decrease in liver blood flow.