Effect of Ursolic Acid on Breast Cancer Resistance Protein-mediated Transport of Rosuvastatin In Vi v o and Vitro

Objective To evaluate whether ursolic acid can inhibit breast cancer resistance protein （BCRP）-mediatedtransport of rosuvastatin in vivo and in vitro. Methods Firstly, we explored the pharmacokinetics of 5-fluorouracil （5-FU, a substrate ofBCRP） in rats in the presence or absence of ursolic acid. Secondly, we studied the pharmacokinetics ofrosuvastatin in rats in the presence or absence of ursolic acid or Ko143 （inhibitor of BCRP）. Finially, theconcentration-dependent transport of rosuvastatin and the inhibitory effects of ursolic acid and Ko143were examined in Madin-Darby Canine Kidney （MDCK） II-BCRP421CC （wild type） cells andMDCK II -BCRP421AA （mutant type） cells. Results As a result, significant changes in pharmacokinetics parameters of 5-FU were observedin rats following pretreatment with ursolic acid. Both ursolic acid and Ko143 could significantly affectthe pharmacokinetics of rosuvastatin. The rosuvastatin transport in the BCRP overexpressing system wasincreased in a concentration-dependent manner. However, there was no statistical difference inBCRP-mediated transport of rosuvastatin betweent the wild type cells and mutant cells. The same asKo143, ursolic acid inhibited BCRP-mediated transport of rosuvastatin in vitro. Conclusion Ursolic acid appears to be a potent modulator of BCRP that affects the pharmacokineticof rosuvastatin in vivo and inhibits the transport of rosuvastatin in vitro.