DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN MRP2-DEFICIENT TR–RATS
| Autor: | Kari T. Kivistö, Klaus-Uwe Möritz, Konrad Meissner, Olaf Grisk, Ute Hofmann, Michel Eichelbaum, Katja A. Arnold, Heyo K. Kroemer, Dieter Lutjöohann, Klaus von Bergmann, Ingrid Klöting, Christoph A. Ritter |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Administration Oral Pharmaceutical Science Lathosterol Pharmacology Intestinal absorption Excretion chemistry.chemical_compound Pharmacokinetics Oral administration polycyclic compounds Animals Medicine Gene Silencing Biliary Tract Pravastatin Cholesterol business.industry nutritional and metabolic diseases Hydroxymethylglutaryl-CoA reductase Rats Intestinal Absorption chemistry Rats Inbred Lew Area Under Curve Injections Intravenous ATP-Binding Cassette Transporters lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors business Half-Life medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 33:1593-1596 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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