HEPATOSELECTIVE CARRIER-MEDIATED SODIUM-INDEPENDENT UPTAKE OF PRAVASTATIN AND PRAVASTATIN-LACTONE

Pravastatin and pravastatin-lactone are not taken up into extrahepatic cells such as fibroblasts, or hepatoma cells such as AS-SOD ascites h epatoma cells or FAO cells. In contrast, pravastatin is taken up into isolated rat hepatocytes by a carrier mediated, saturable, temperature -dependent and energy-dependent mechanism. The kinetic parameters for the saturable uptake are K-m 27 mu M, V(max)537 pmol/mg per min. The p ermeability coefficients were determined to be 9.829.10(-7) cm/s at 4 degrees C, 1.76.10(-6) cm/s at 7 degrees C, 3.85.10(-6) cm/s at 17 deg rees C and 5.82.10(-6) cm/s at 37 degrees C. The activation energy is 60 kJ/mol for 100 mu M pravastatin at 37 degrees C. The Q(10) values a re between 1.7 and 2.8. In the presence of metabolic inhibitors and in the absence of oxygen, transport is inhibited. Uptake of pravastatin is not dependent on an extracellular to intracellular sodium-gradient. Replacement of chloride by sulfate, nitrate, gluconate or thiocyanate significantly inhibits the uptake of pravastatin. Uptake is competiti vely inhibited by cholate and taurocholate in the presence and absence of sodium. Pravastatin, however, competitively inhibits the uptake of cholate and taurocholate only in the absence of sodium. In addition, pravastatin-lactone enters liver cells via an energy-dependent, carrie r-mediated uptake system. For the saturable energy-dependent part of t he hepatocellular uptake a K-m value of 9 mu M and a V-max value of 62 1 pmol/mg per min was determined. The permeability coefficient of prav astatin-lactone uptake is calculated to be 5.41.10(-6) cm/s at 37 degr ees C. The uptake of pravastatin-lactone is competitively-noncompetiti vely inhibited by pravastatin and by lovastatin and vice versa. These results indicate that the hepatoselectivity of pravastatin is due to i ts carrier-mediated uptake into rat hepatocytes via a sodium-independe nt bile acid carrier. Pravastatin-lactone resembles pravastatin-sodium in its hepatoselectivity.