DISPOSITION OF ORAL AND INTRAVENOUS PRAVASTATIN IN MRP2-DEFICIENT TR^–RATS

Abstract

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.

Pharmacokinetic interaction between pravastatin and olmesartan in relation to SLCO1B1 polymorphism

“…Recent in vitro studies indicated that organic anion transporter 3 (OAT3) expressed at the basolateral membrane of renal proximal tubule epithelial cells is predominantly involved in renal uptake of both pravastatin and olmesartan (Hasegawa et al 2002;Yamada et al 2007). The drug-drug interaction via OAT3 between pravastatin and olmesartan may account for the reduction of olmesartan renal excretion in the co-administration phase; however, the interaction via MRP2, which also is expressed in the kidney, cannot be ruled out (Kivistö et al 2005;Nakagomi-Hagihara et al 2006). …”

“…Taking these into consideration, increased AUC and decreased CL t /F of olmesartan in the co-administration phase are unlikely to result from the inhibition of CYP-mediated metabolism of olmesartan by pravastatin. However, possible interaction via other transporters, multidrug resistance-associated protein 2 (MRP2) in particular, cannot be negligible, because pravastatin and olmesartan are also a substrate of MRP2, and this transporter is reported to be involved in their biliary excretion (Kivistö et al 2005;Nakagomi-Hagihara et al 2006). No significant intergenotypic differences in the mean Ae 0-24 and CLr 0-24 values of olmesartan were observed in both the single-dose and co-administration phases; however, these values in the single-dose phase were decreased after co-administration of pravastatin, irrespective to SLCO1B1 status (Table 1).…”

“…Pravastatin is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase used for the treatment of hypercholesterolemia. Although pravastatin is not significantly metabolized by cytochrome P450 (CYP) isoenzymes, cumulative evidence has suggested that multiple membrane transporters are involved in the absorption (Kobayashi et al 2003), hepatobiliary excretion (Hirano et al 2005;Kivistö et al 2005;Nakai et al 2001), and renal excretion (Hasegawa et al 2002) of pravastatin. Organic anion transporting polypeptide (OATP) 1B1 (gene SLCO1B1) is an uptake transporter expressed at the sinusoidal membrane of hepatocytes, mediating the uptake of various endogenous and exogenous substances from the blood circulation into hepatocytes in a sodium-independent manner.…”

Duodenum-triggered delivery of pravastatin sodium: II. Design, appraisal and pharmacokinetic assessments of enteric surface-decorated nanocubosomal dispersions

“…On the study day, the overnight (12 h) fasted rats of group I were orally treated with an aqueous PVS solution (treatment A) equivalent to 20 mg/kg while those of Group II were orally administered with E-F8 cubosomes (treatment B) at the same dose (Kivistö et al, 2005).…”

Co-administration of paroxetine and pravastatin causes deregulation of glucose homeostasis in diabetic rats via enhanced paroxetine exposure

“…Our results showed that coadministration of paroxetine markedly decreased the hepatic uptake of pravastatin ( Figure 7G), which may become a reason that paroxetine weakened the cholesterol-lowering effects of pravastatin ( Figure 1C). Although the transport of pravastatin from the blood into the bile is mainly mediated by Mrp2 [46,47] , data from QT-PCR showed that drug treatment did not disrupt the effects of DM on Mrp2 mRNA levels, excluding the possibility that Mrp2 mRNA levels might explain the increased exposure to pravastatin by coadministration of paroxetine.…”