Received for publication June 28, 2005.
Revised August 7, 2005.
Accepted for publication August 17, 2005.

DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN Mrp2-DEFICIENT TR- RATS

Abstract

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 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 CL of pravastatin was 4.6-fold higher (39.2 vs 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 vs 3.29 l/kg, p < 0.01) in the wild-type rats. The mean CL_R of pravastatin in the TR- rats was 16.5-fold increased as compared with the wild-type animals (0.695 vs 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 HMG-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. Further, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.

Key words: ABC transporters, biliary excretion, bioavailability, drug absorption, drug clearance, drug disposition, hepatobiliary transport, renal elimination, transgenic models, transporters