标题：Dose-Dependent Hepatic Handling of l-Propranolol Determined by Multiple Indicator Dilution Method : Influence of Tissue Binding of l-Propranolol on Its Hepatic Elimination
摘要：Concentration-dependency in the hepatic elimination of l-propranolol (l-PR) was investigated over a wide range of concentrations from 60 to 2200 μM in an isolated rat liver perfusion system. Under the steady-state condition produced by unlabeled l-PR at various concentrations, 3H-l-PR and 14C-inulin were bolusly injected into the portal vein, and the outflow was collected at 0.5 s intervals over 30 s. Up to 300 μM, the instantaneous hepatic availability of l-PR was approximately 4%, while it abruptly increased when the perfusate concentration exceeded 300 μM. To determine which process (influx or efflux or sequestration process) caused the nonlinearity, we calculated the rate constants k1 (influx), k2 (efflux), and k3 (sequestration) based on the "distributed" model. With increasing l-PR concentration in the perfusate, k2 increased approximately two times, whereas k3 decreased to approximately one-half. In contrast, k1 was independent of the perfusate concentration. The concentration-dependency of k2 was explained by saturation of l-PR tissue binding, since the tissue unbound fraction of l-PR obtained with liver homogenates and isolated hepatocytes increased approximately two times. The efflux and sequestration clearances were then normalized by the unbound fractions in the liver. The efflux clearance for unbound l-PR was constant irrespective of the perfusate concentration, whereas the sequestration clearance for unbound l-PR (CLint) showed Michaelis-Menten type saturation (Km=28 μM, Vmax=2.8 μmol/min/g liver, α (nonspecific) = 20 ml/min/g liver). Based on the comparison of the kinetic parameters representing these processes, the rate-determining process for the hepatic clearance of l-PR is a combination of the membrane transport and sequestration processes at low concentrations, while at high concentration, the rate-determining process is the "sequestration" process. Such concentration dependent shift of the rate determining process can be attributed to the saturation of its tissue binding as well as to the sequestration process.
