Nimesulide (NIM) is a classic nonsteroidal anti-inflammatory drug. However, some patients treated with NIM experienced cholestatic liver injury. For this reason, we investigated the potential mechanism underlying NIM-induced cholestasis by using in vivo and in vitro models. Oral administration of 100 mg/kg/day NIM to Wistar rats for 5 days increased the levels of plasma total bile acids, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase by 1.49-, 1.31-, 1.60-, and 1.29-fold, respectively. In sandwich-cultured rat hepatocytes, NIM and 4′-hydroxynimesulide (M1) reduced the biliary excretion index of d8-taurocholic acid (d8-TCA) and 5 (and 6)-carboxy-2ʹ,7ʹ-dichlorofluorescein in a concentration-dependent manner, indicating the inhibition of the efflux transporters bile salt export pump and multidrug resistance–associated protein 2, respectively. In suspended rat hepatocytes, NIM and M1 inhibited the uptake transporters of d8-TCA for Na+-taurocholate cotransporting polypeptide at IC50 values of 21.3 and 25.0 μM, respectively, and for organic anion-transporting proteins at IC50 values of 45.6 and 39.4 μM, respectively. By contrast, nitro-reduced NIM and the further acetylated metabolite did not inhibit or only marginally inhibited these transporters at the maximum soluble concentrations. Inhibitory effects of NIM and M1 on human bile acid transporters were also confirmed using sandwich-cultured human hepatocytes. These data suggest that the inhibition of bile acid transporters by NIM and M1 is one of the biologic mechanisms of NIM-induced cholestasis.
- Received October 26, 2016.
- Accepted February 8, 2017.
This work was supported by the National Natural Science Foundation of China [Grants 81573500 and 81503153]. The authors declare no conflicts of interest.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics