PT  - JOURNAL ARTICLE
AU  - Kivistö, Kari T.
AU  - Grisk, Olaf
AU  - Hofmann, Ute
AU  - Meissner, Konrad
AU  - Möritz, Klaus-Uwe
AU  - Ritter, Christoph
AU  - Arnold, Katja A.
AU  - Lutjöohann, Dieter
AU  - von Bergmann, Klaus
AU  - Klöting, Ingrid
AU  - Eichelbaum, Michel
AU  - Kroemer, Heyo K.
TI  - DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN MRP2-DEFICIENT TR<sup>–</sup> RATS
AID  - 10.1124/dmd.105.006262
DP  - 2005 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1593--1596
VI  - 33
IP  - 11
4099  - http://dmd.aspetjournals.org/content/33/11/1593.short
4100  - http://dmd.aspetjournals.org/content/33/11/1593.full
SO  - Drug Metab Dispos2005 Nov 01; 33
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics