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SHORT COMMUNICATION

DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN MRP2-DEFICIENT TR^– RATS

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (K.T.K, U.H., K.A.A., M.E.); Department of Physiology, Ernst-Moritz-Arndt University Greifswald, Karlsburg, Germany (O.G.); Department of Pharmacology, Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany (K.M., K.-U.M., C.R., H.K.K.); Department of Clinical Pharmacology, University of Bonn, Bonn, Germany (D.L., K.v.B.); and Department of Laboratory Animal Science, Ernst-Moritz-Arndt University Greifswald, Karlsburg, Germany (I.K.)

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR^– rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR^– animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR^– rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR^– rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR^– rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR^– rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.

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