Abstract

The relative contributions of tissue uptake and metabolism to the dose-dependent clearance of propranolol by the perfused rat liver have been investigated. When a small dose (1 mg) was added to a recycling system of 100 ml volume at a flow rate of 20 ml/min, the drug was cleared monoexponentially at a rate compatible with complete hepatic extraction (t_½ = 3.5 min). With larger doses of 5 and 10 mg, drug concentrations declined biexponentially. The early rapid (α) decline gave a t_½ of 3.2 min and later (β) elimination was more prolonged but remained first order (t_½ = 14 min). The extraction of low doses and the α-phase of high doses was attributed to high-affinity tissue binding as it was unaffected when metabolism was inhibited by SKF 525-A (100 mg/kg ip 1 hr before perfusion). This high-affinity binding site became saturated when 3.8 mg had been removed from the reservoir, giving total liver drug concentrations of about 400 µg/g liver. Following a 10-mg bolus, steady state was maintained by an infusion calculated to replace only that drug lost during the β-phase. During the β-phase after single doses of 5 and 10 mg, hepatic tissue binding increased with time and, while hepatic removal rate was proportional to the inflow propranolol concentration, it was not a linear function of the drug concentration in the venous effluent. The effect of saturable tissue binding on the rate of metabolism was investigated by following the fate of unchanged propranolol bound in the liver during washout with drug-free perfusate. It was found that the rate of metabolism of the calculated free drug in the liver exhibited saturation at a time when metabolic rate was linear with respect to total liver concentration. Such binding-dependent, pseudo-first-order elimination is offered as an explanation of the exponential removal of drug from the reservoir during the β-phase of elimination of high doses. It is suggested that the nonlinear hepatic tissue binding is an important determinant of the unusual dose-dependent kinetics of elimination of propranolol.