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Aim To investigate the metabolic drug-drug interaction (DDI) potential of rhein through CYP450.Methods Specific substrates of CYP1A, CYP2C, CYP2D, CYP3A and CYP2E were incubated with Rhein (RE) in human liver microsomes (HLMs) and in rat liver microsomes (RLMs).The inhibition constants (Ki) of RE were used to predict potential DDIs in vivo using the equation AUCi/AUC =1+ [I]/Kj.The effects of RE on the activities of two CYP enzymes in rats were studied for verification.Results In our study, RE appeared to be a strong inhibitor of human liver CYP2E1 with IC50 values of 9.2 μM, and exhibited moderate inhibition (10 μM < IC50 values < 70 μM) of the other human liver CYP enzymes and rat liver CYP1A, CYP2C, CYP3A, and CYP2E.However, both the in vivo/in vitro prediction and in vivo rat experiments confirmed that it was less likely or unlikely that there was the metabolic drug-drug interaction (DDI) potential of rhein through CYP450, which might be causedby the low free concentration of RE in vivo due to the high protein binding rate.Conclusion It can be concluded that RE has a relatively low metabolic DDI potential towards co-administered drugs in rats and in humans, supported by its high plasma protein binding and subsequently low concentration of free RE.