Pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, in rat

Abstract

1. The pharmacokinetics and disposition of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, were investigated following single administration of (14)C-rosuvastatin in the Sprague-Dawley rat. 2. Following oral administration of (14)C-rosuvastatin at 1, 5 and 25 mg kg(-1), the C(max) and AUC of the radioactivity in the plasma increased more than the increase in dose ratio. 3. Excretion of radioactivity was 98.0% of the dose in the faeces and 0.4% in the urine up to 168 h after oral administration in the intact rat, and was 55.1% in the bile and 0.5% in the urine up to 48 h post-dosing in the bile duct-cannulated rat. The unchanged compound mainly accounted for the radioactivity in the bile and faeces. 4. In the tissue distribution study, the concentration of the radioactivity in the liver was markedly higher than those in the other tissues, and the radioactivity concentration ratios of the liver to the plasma were between 8 and 25 up to 48 h after oral administration. The liver-specific distribution of rosuvastatin was similarly recognized in whole-body autoradiography. 5. Metabolic profiling studies indicated that rosuvastatin would not be metabolized by CYP enzymes. 6. These results clarified that rosuvastatin selectively distributed in the liver - the target organ - and was excreted in the bile mainly as the unchanged compound.

Integrated Approach of In Vivo and In Vitro Evaluation of the Involvement of Hepatic Uptake Organic Anion Transporters in the Drug Disposition in Rats Using Rifampicin as an Inhibitor

“…The CL renal,p of pravastatin was observed with 14% of total plasma clearance. This is concordant with the report indicating that in rats pravastatin is eliminated from the kidneys as well as the liver (Takada et al, 2004) while other statins are predominantly eliminated from the liver (Boberg et al, 1998;Nezasa et al, 2002;Watanabe et al, 2010). Taken together, these findings indicate that the involvement of Oatps in vivo can be assessed by comparing the nonrenal clearance of test compounds or for compounds with minimal renal excretion by comparing the total clearance between the presence and absence of rifampicin.…”

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

“…The mean steady-state RSV maximum total plasma concentration in humans is ∼50 ng/ ml (0.1 mM) after an 80-mg daily oral dose (Warwick et al, 2000;Cooper et al, 2003). Accumulation (Kp) of total RSV in human and rat hepatocytes in vitro was ∼20-fold in the present study, consistent with previous reports (Nezasa et al, 2003), and ∼20-to 45-fold accumulation in rat liver in vivo (Nezasa et al, 2002), leading to estimated hepatocellular RSV concentrations of #5 mM in humans. At present, the contribution of other transport proteins and passive diffusion to RSV CL BL in SCH cannot be ruled out because specific MRP4 inhibitors have not been identified.…”

Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects

“…Ketoconazole is known to have inhibitory effects on the transport protein P-gp [16]. Active-or facilitated-transport processes may have a role in the absorption and disposition of rosuvastatin [17,18]. The identity of the rosuvastatin transporters that interact with rosuvastatin has not been clearly defined, but if it were a P-gp substrate, an increase in rosuvastatin exposure would be expected following coadministration with ketoconazole.…”

“…Active-or facilitated-transport processes may have a role in the absorption and disposition of rosuvastatin. Thus, studies with rats have demonstrated selective hepatic uptake of rosuvastatin by an active transport process [17], and rosuvastatin was shown to be a ligand for a liver-specific human organic-anion-transporting polypeptide present in the basolateral membranes of hepatic cells [18], although the identity of these transporters has not yet been clearly defined. Thus, the results of the present study may provide an indication of whether P-gp-mediated transport contributes to rosuvastatin disposition.…”