Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil

Abstract

ABSTRACT:The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n ‫؍‬ 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n ‫؍‬ 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 ؎ 3.5 and 35.7 ؎ 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC bile /AUC VH ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC 50 values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 ؎ 0.06; TII, 0.46 ؎ 0.13) and increased the AUC VP and AUC VH by 1.6-and 9.1-fold, respectively. In addition, the biliary exposure and f e, bile were reduced by Ϸ50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters.Drug-drug interactions (DDIs) involving rosuvastatin that result in increased plasma exposure of rosuvastatin might, in rare cases, result in severe unwanted side effects such as myopathy and possibly rhabdomyolysis (Thompson et al., 2003). A 7.1-and 10.6-fold increase in the plasma exposure (AUC) and maximum plasma concentration (C max ) of a single 10-mg oral rosuvastatin dose was observed in heart transplant patients receiving cyclosporine treatment (75-200 mg b.i.d.) (Simonson et al., 2004). In addition, gemfibrozil (600 mg b.i.d.) increased the AUC and C max of a single 80-mg rosuvastatin dose by 1.88-and 2.21-fold, respectively .These clinically relevant DDIs are considered to involve inhibition of hepatic transport proteins although the in vivo relevant mechanism(s) remains to be elucidated. High hepatic exposure is essential for rosuvastatin, which exhibits its pharmacological effects by inhibiting HMG-Co A reductase, localized to the endoplasmic reticulum of the hepatocyte. Rosuvastatin has an estimated hepatic extraction of 0.63 in humans and the hepatic clearance accounts for approximately 70% of the total plasma clearance (Martin et al., 2003a). OATP1B1 (SLCO1B1) is reported to be the primary transporter involved; however, additional sinusoidal transporters...

Effects of Ketoconazole on the In Vivo Biotransformation and Hepatobiliary Transport of the Thrombin Inhibitor AZD0837 in Pigs

“…To approximate the secretion of the compounds in the entire small intestine, the amounts secreted into the 10-cm segment (Ae intestine ) were scaled by a factor of 50, estimating the length of the porcine small intestine to 5 m and assuming no changes in the transport processes along this path (Bergman et al, 2009). These scaled amounts were used to approximate the intestinal clearance (CL intestine ) (eq.…”

“…With regard to metabolism, it has been shown to be a suitable model of human CYP3A, displaying enzymatic activity toward prototypical substrates similar to that of the human isoforms (Soucek et al, 2001;Anzenbacherová et al, 2005;Thörn et al, 2009). The literature on transport proteins in pigs is less detailed, but several drug-relevant transporters are known to be expressed in pigs, and drugs dependent on carrier-mediated transport in their clinical disposition have been shown to display similar in vivo pharmacokinetics in pigs and humans (Goh et al, 2002;Török et al, 2003;Sjödin et al, 2008;Bergman et al, 2009). Resolving the causes of the pharmacokinetic interaction between AZD0837 and ketoconazole would lead to improved knowledge about processes that are important for the disposition of AZD0837 and its metabolites and for the prediction of other plausible drug-drug interactions.…”

Evaluation of Rosuvastatin as an Organic Anion Transporting Polypeptide (OATP) Probe Substrate: In Vitro Transport and In Vivo Disposition in Cynomolgus Monkeys

“…Furthermore, for most transporters, the expression in the liver tissues was comparable to that in the cryopreserved hepatocytes (Wang et al, 2015). In addition to in vitro assessment, RSV has often been used for kinetic studies in vivo in several species, including humans Simonson et al, 2004;Prueksaritanont et al, 2014), monkeys (Shen et al, 2013), mice (Salphati et al, 2014), rats (Wen and Xiong, 2011), and pigs (Bergman et al, 2009). When compared with rodents, however, the absorption, distribution, metabolism, and excretion (ADME) profile of RSV in nonhuman primates has not been studied extensively (Nezasa et al, 2002b;Martin et al, 2003b).…”

In Vivo Investigation in Pigs of Intestinal Absorption, Hepatobiliary Disposition, and Metabolism of the 5α-Reductase Inhibitor Finasteride and the Effects of Coadministered Ketoconazole

“…The pigs were anesthetized, and surgery was performed according to previously described methods (Petri et al, 2006;Sjödin et al, 2008;Bergman et al, 2009). The body temperature, blood gases, blood pH, hematocrit, arterial and central venous pressures, heart rate, and electrocardiographic parameters were continuously monitored during the entire experiment.…”

“…The pig model enables sampling from the portal vein (VP), the hepatic vein (VH), and the femoral vein (VF) and bile collection directly from the biliary duct. This has made it possible to perform in-depth investigations on the effects of several DDIs on intestinal absorption, intestinal metabolism, liver metabolism, and hepatobiliary disposition (Petri et al, 2006;Sjödin et al, 2008;Bergman et al, 2009;Thörn et al, 2009). In this study, the model was used to examine in detail the effects of ketoconazole-inhibited CYP3A-mediated metabolism on the PK of finasteride.…”