title: Hepatoselective carrier-mediated sodium-independent uptake of pravastatin and pravastatin-lactone.
abstract: Pravastatin and pravastatin-lactone are not taken up into extrahepatic cells such as fibroblasts, or hepatoma cells such as AS-30D ascites hepatoma 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 Km 27 microM, Vmax 537 pmol/mg per min. The permeability coefficients were determined to be 9.829 x 10(-7) cm/s at 4 degrees C, 1.76 x 10(-6) cm/s at 7 degrees C, 3.85 x 10(-6) cm/s at 17 degrees C and 5.82 x 10(-6) cm/s at 37 degrees C. The activation energy is 60 kJ/mol for 100 microM pravastatin at 37 degrees C. The Q10 values are 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 competitively 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, carrier-mediated uptake system. For the saturable energy-dependent part of the hepatocellular uptake a Km value of 9 microM and a Vmax value of 621 pmol/mg per min was determined. The permeability coefficient of pravastatin-lactone uptake is calculated to be 5.41 x 10(-6) cm/s at 37 degrees C. The uptake of pravastatin-lactone is competitively-noncompetitively inhibited by pravastatin and by lovastatin and vice versa. These results indicate that the hepatoselectivity of pravastatin is due to its carrier-mediated uptake into rat hepatocytes via a sodium-independent bile acid carrier. Pravastatin-lactone resembles pravastatin-sodium in its hepatoselectivity.
authors.affiliation: Institut für Pharmakologie und Toxikologie der Justus-Liebig Universität, Giessen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Ziegler
authors.forename: S
authors.initials: S
authors.lastname: Hummelsiep
mesh_terms: D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D007700:Kinetics; D007783:Lactones / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D017035:Pravastatin / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured
chemical_list: D007783:Lactones; D017035:Pravastatin