Abstract
Among the HMG-CoA reductase inhibitors, pravastatin which is hydrophilic in nature, has been shown to exhibit relatively specific inhibition of cholesterol synthesis in the liver. As one of the reasons for this relatively specific pharmacological activity, we demonstrated that the tissue distribution of pravastatin is limited because of its high hydrophilicity, while hepatic uptake by active transport mechanism via multispecific anion transporter takes place at the liver surface. We examined the hepatic elimination of HMG-CoA reductase inhibitor, pravastatin, at steady-state by measuring the plasma concentration in both arterial (Ca, ss) and hepatic venous (Chv, ss) blood. The hepatic extraction ratio at steady-state showed a clear decrease with increasing pravastatin infusion rate. The total hepatic elimination velocity (V) at steady-state exhibited the Michaelis-Menten type saturation with the mean logarithmic concentration (C), which is used in the parallel-tube model, and the values of Km and Vmax estimated from the plot of V vs. C were comparable with those obtained from the analysis of the initial uptake velocity using isolated hepatocytes. This result indicates that overall intrinsic clearance (CLint, all) was regulated by the uptake process, since pravastatin was efficiently taken up by an active transport mechanism followed by rapid metabolism and/or biliary excretion. Pravastatin is a typical drug whose clearance in the liver, which is the target organ in terms of its pharmacological effect as well as the major organ for its pharmacokinetics in the whole body, is governed mainly by an uptake process mediated by active transport.
