RT Journal Article SR Electronic T1 Organic anion transporting polypeptides (OATPs)-mediated drug-drug interaction study between rosuvastatin and cyclosporine A in chimeric mice with humanized liver JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.117.075994 DO 10.1124/dmd.117.075994 A1 Masashi Uchida A1 Yoriko Tajima A1 Masakazu Kakuni A1 Yutaka Kageyama A1 Taro Okada A1 Eri Sakudara A1 Chise Tateno A1 Ryoji Hayashi YR 2017 UL http://dmd.aspetjournals.org/content/early/2017/10/19/dmd.117.075994.abstract AB The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP-inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP-substrate, by 7.1-fold in clinical studies. PXB-mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes, and have been widely used for drug discovery in DMPK studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB-mice and fresh human hepatocytes (PXB-cells) obtained from PXB-mice. We initially investigated the active transport of rosuvastatin into PXB-cells, and found concentration-dependent uptake with Km of 4.0 μmol/L and Vmax of 4.63 pmol/min/106 cells. Cyclosporine A inhibited the uptake of rosuvastatin with IC50 of 0.21 μmol/L. We then examined in vivo DDIs, and the exposure of orally administered rosuvastatin increased by 3.3- and 11-fold in PXB-mice pretreated with 10 and 50 mg/kg of cyclosporine A, whereas by 2.5- and 6.2-fold when rosuvastatin was administered intravenously, that were conducted for considering gastrointestinal DDIs. The liver-to-blood concentration ratio of rosuvastatin was dose-dependently decreased by a pretreatment with cyclosporine A in PXB-mice and SCID mice. Observed DDIs in vivo were considered to be reasonable based on the estimated concentrations of cyclosporine A at the inlet to the liver and in the liver tissues of both mice. In conclusion, our results indicate that PXB-mice might be a useful tool for predicting human OATPs-mediated DDIs in drug discovery, and also its limitation due to the differences of gastrointestinal condition from human should be considered.