Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains Iovastatin (Lv) for hyperlipidemia treatment,although it has fewer side effects than Lv.However,the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear.Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia.We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg,i.g.) and found that HFD remarkably decreased the active form of Lv (the Iovastatin acid,LvA) exposure in the circulation system,especially in the targeting organ liver,with a declined conversion from Lv to LvA,whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased.Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg,i.g.) or an equivalent dose of Lv (10 mg/kg,i.g.).A higher exposure of LvA and lower exposure of Lv were observed after XZK administration,suggesting a pharmacokinetic interaction of some ingredients in XZK.Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver,thus contributing to the lower transformation of Lv into LvA.In contrast,XZK inhibited the inflammation and upregulated CES in the intestine and the liver,Finally,we evaluated the effects of monacolins and phytosterols,the fractional extracts of isoflavones,on inflammatory LS174T or HepG2 cells,which showed that isoflavones inhibited inflammation,upregulated CES,and markedly enhanced the conversion of Lv into LvA.For the first time,we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.