Organic Anion–Transporting Polypeptide (OATP)–Mediated Drug-Drug Interaction Study between Rosuvastatin and Cyclosporine A in Chimeric Mice with Humanized Liver

Abstract

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 drug metabolism and pharmacokinetics 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 a Michaelis-Menten constant value of 4.0 mol/l and a value of 4.63 pmol/min per 10 cells. Cyclosporine A inhibited the uptake of rosuvastatin with an IC value of 0.21 mol/l. We then examined in vivo DDIs, and the exposure of orally administered rosuvastatin increased by 3.3-fold and 11-fold in PXB mice pretreated with 10 and 50 mg/kg cyclosporine A, whereas it increased by 2.5-fold and 6.2-fold when rosuvastatin was administered intravenously, in studies that were conducted for considering gastrointestinal DDIs. The liver-to-blood concentration ratio of rosuvastatin was dose-dependently decreased by 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 OATP-mediated DDIs in drug discovery, and its limitation due to the differences of gastrointestinal condition from human should also be considered.

Scutellarin inhibition of the rosuvastatin uptake in rat hepatocytes and the competition for organic anion transporting polypeptide 1B1 in HEK293T cells

“…Early studies have found that cyclosporine A can inhibit OATP1B1-mediated transport of cerivastatin, which increases the concentration of cerivastatin in vivo and changes the distribution of cerivastatin in vivo 22 . OATP mediates rosuvastatin transportation, cyclosporine A can competitively inhibit the uptake of rosuvastatin by the hepatocyte membrane OATP and thus increases drug plasma concentration 23 . Studies have also found that Salvianic acid A can inhibit OATP1B1 by competition, thus affecting the pharmacokinetic characteristics of rosuvastatin in rats 24 .…”

Art of Making Artificial Liver: Depicting Human Liver Biology and Diseases in Mice

“…258,259 Lastly, the drug-drug interactions-which are caused by competition over CYP enzymes, non-CYP enzymes, and transporters-occurring in the liver of HLCM well resemble that of the human liver. 97,[260][261][262] Collectively, HLCM most accurately reiterates the DMPK of the human liver and justifies its superiority over other in vitro and in vivo study tools. 96,263,264 Drug-Induced Liver Injury…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…Quinidine has been shown to inhibit the CYP2D6‐mediated metabolism of debrisoquin, and ritonavir has been reported to reduce the CYP3A4‐mediated metabolism of clemizole in humanized mice (Katoh et al, ; Nishimura et al, ). In a transporter DDI study in humanized mice, cyclosporine A effectively inhibited the OATP‐mediated uptake of rosuvastatin in a dose dependent manner (Uchida et al, ). Similar to humans, the humanized mice gave a higher oral plasma AUC than for intravenous administration, suggesting the gut contribution to DDI.…”

“…Similar to humans, the humanized mice gave a higher oral plasma AUC than for intravenous administration, suggesting the gut contribution to DDI. However, the presence of mouse gut transporters complicated the data interpretation of liver OATP DDI (Uchida et al, ).…”