title: 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 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.
authors.affiliation: Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. kari.kivisto@ikp-stuttgart.de
authors.forename: Kari T
authors.initials: KT
authors.lastname: Kivistö
authors.forename: Olaf
authors.initials: O
authors.lastname: Grisk
authors.forename: Ute
authors.initials: U
authors.lastname: Hofmann
authors.forename: Konrad
authors.initials: K
authors.lastname: Meissner
authors.forename: Klaus-Uwe
authors.initials: KU
authors.lastname: Möritz
authors.forename: Christoph
authors.initials: C
authors.lastname: Ritter
authors.forename: Katja A
authors.initials: KA
authors.lastname: Arnold
authors.forename: Dieter
authors.initials: D
authors.lastname: Lutjöohann
authors.forename: Klaus
authors.initials: K
authors.lastname: von Bergmann
authors.forename: Ingrid
authors.initials: I
authors.lastname: Klöting
authors.forename: Michel
authors.initials: M
authors.lastname: Eichelbaum
authors.forename: Heyo K
authors.initials: HK
authors.lastname: Kroemer
mesh_terms: 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
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017035:Pravastatin