Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.
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.
Kivistö
Kari T
KT
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. kari.kivisto@ikp-stuttgart.de
Grisk
Olaf
O
Hofmann
Ute
U
Meissner
Konrad
K
Möritz
Klaus-Uwe
KU
Ritter
Christoph
C
Arnold
Katja A
KA
Lutjöohann
Dieter
D
von Bergmann
Klaus
K
Klöting
Ingrid
I
Eichelbaum
Michel
M
Kroemer
Heyo K
HK
D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001659:Biliary Tract / Q000378:metabolism; D020868:Gene Silencing; D006207:Half-Life; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D017035:Pravastatin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D011917:Rats, Inbred Lew
D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin