Murine Oatp1a/1b Uptake Transporters Control Rosuvastatin Systemic Exposure Without Affecting Its Apparent Liver Exposure

Abstract

Organic anion-transporting polypeptides (OATPs) mediate the liver uptake and hence plasma clearance of a broad range of drugs. For rosuvastatin, a cholesterol-lowering drug and OATP1A/1B substrate, the liver represents both its main therapeutic target and its primary clearance organ. Here we studied the impact of Oatp1a/1b uptake transporters on the pharmacokinetics of rosuvastatin using wild-type and Oatp1a/ 1b-null mice. After oral administration (15 mg/kg), intestinal absorption of rosuvastatin was not impaired in Oatp1a/1b-null mice, but systemic exposure (area under the curve) was 8-fold higher in these mice compared with wild-type. Although liver exposure was comparable between the two mouse strains (despite the increased blood exposure), the liver-to-blood ratios were markedly decreased (.10-fold) in the absence of Oatp1a/1b transporters. After intravenous administration (5 mg/kg), systemic exposure was 3-fold higher in Oatp1a/1b-null mice than in the wild-type mice. Liver, small intestinal, and kidney exposure were slightly, but not significantly, increased in Oatp1a/1b-null mice. The biliary excretion of rosuvastatin was very fast, with 60% of the dose eliminated within 15 minutes after intravenous administration, and also not significantly altered in Oatp1a/1b-null mice. Rosuvastatin renal clearance, although still minor, was increased ∼15-fold in Oatp1a/1b-null males, suggesting a role of Oatp1a1 in the renal reabsorption of rosuvastatin. Absence of Oatp1a/1b uptake transporters increases the systemic exposure of rosuvastatin by reducing its hepatic extraction ratio. However, liver concentrations are not significantly affected, most likely due to the compensatory activity of high-capacity, low-affinity alternative uptake transporters at higher systemic rosuvastatin levels and the absence of efficient alternative rosuvastatin clearance mechanisms.

Utility of Oatp1a/1b-Knockout and OATP1B1/3-Humanized Mice in the Study of OATP-Mediated Pharmacokinetics and Tissue Distribution: Case Studies with Pravastatin, Atorvastatin, Simvastatin, and Carboxydichlorofluorescein

“…Evidence exists for expression of the oatp1a subfamily in the renal proximal tubule (Iusuf et al, 2012b), and this was supported at a functional level in the present study by the modest decreases (1.4-to 2.9-fold) in atorvastatin and simvastatin kidney distribution. Quantitatively, these findings are consistent with the previously reported #3-fold decrease in rosuvastatin and 2-fold decrease in fexofenadine kidney distribution in oatp1a/1b-knockout mice (van de Steeg et al, 2010;Iusuf et al, 2013). Surprisingly, pravastatin renal tissue distribution was markedly increased 2 orders of magnitude in oatp1a/1b-knockout mice, and this increase was partially attenuated in humanized mice.…”

“…To date, a total of five studies of OATP substrate disposition in these knockout and transgenic models have been published, which are conceptually consistent with the current findings of altered systemic pharmacokinetics and hepatic drug distribution (van de Steeg et al, 2010(van de Steeg et al, , 2011(van de Steeg et al, , 2012Iusuf et al, 2012aIusuf et al, , 2013. Specifically, pravastatin, rosuvastatin, and fexofenadine were studied in oatp1a/1b-knockout mice, whereas paclitaxel and methotrexate disposition was examined across both knockout and OATP-humanized mice.…”

“…Previously reported alterations in pravastatin pharmacokinetics in oatp1a/1b2/2 mice are quantitatively in good agreement with the present findings: intravenous exposure was increased 4-fold, oral exposure 30-fold, and liver distribution was 10-to 100-fold decreased (Iusuf et al, 2012a); in the present study, these changes were 4-, 115-, and 196-fold, respectively. Rosuvastatin intravenous exposure was 3-fold increased, oral exposure 8-fold increased, and liver distribution was decreased 1 order of magnitude (Iusuf et al, 2013); similarly, fexofenadine intravenous exposure was 3-fold increased and hepatic distribution 10-fold decreased (van de Steeg et al, 2010). Methotrexate intravenous exposure was 3-to 5-fold increased and hepatic distribution was 69-to 131-fold decreased (van de Steeg et al, 2010(van de Steeg et al, , 2011; knockin of individual human OATP isoforms partially restored methotrexate exposure (;2-fold decrease) and increased liver distribution 6-to 15-fold .…”

Evaluation of Organic Anion Transporting Polypeptide 1B1 and 1B3 Humanized Mice as a Translational Model to Study the Pharmacokinetics of Statins

“…4) Differences in the metabolism of these statins in mice and humans, which might obscure the in vivo impact of the OATP1B transporters on drug disposition in the mouse models. The metabolism of rosuvastatin in mice was very limited (Hirano et al, 2005;Kitamura et al, 2008;Iusuf et al, 2013), so that dmd.aspetjournals.org this appears to be an unlikely explanation for rosuvastatin. However, pitavastatin showed more profound hepatic metabolism in mice compared with rats and humans (Fujino et al, 2002).…”

“…3) Potential change of alternative elimination pathways in hOATP1B mice. According to Iusuf et al (2013), renal clearance of rosuvastatin is only 9.4% of total clearance in WT mice. However, renal clearance increased to 29% of total clearance in Oatp1a/1b KO mice, which is similar to humans.…”