Interaction of rhubarb and methotrexate in rats: in vivo and ex vivo approaches.

Rhubarb, the rhizome of Rheum palmatum L. (RP), is a popular herb used in Chinese medicine prescriptions. RP contains a variety of polyphenolic anthraquinones, such as aloe-emodin, rhein, emodin and chrysophanol. Our previous study found that the anthraquinones in RP existed predominantly as glucuronides/sulfates in the bloodstream, which were putative substrates of MRPs. Methotrexate (MTX) is a widely used immunosuppressant and anticancer agent, but it has a narrow therapeutic index. The transcellular transport of MTX is mediated by multidrug resistance associated proteins (MRPs). This study investigated the effects of coadministration of RP on MTX pharmacokinetics in rats. The possible involvement of MRP 2 was verified by using cell models and various typical MRP 2 substrates. The results showed that coadministration of 0.5 mg/kg of RP significantly increased the AUC(0-t) and MRT of MTX by 307% and 364%, and 1.0 g/kg of RP significantly increased the AUC(0-)t and MRT of MTX by 602% and 419%, respectively. Cell line studies indicated that the activity of MRP 2 was inhibited by the metabolites of RP and rhein. In conclusion, concomitant administration of RP markedly increased the systemic exposure of MTX via inhibiting MRP 2-mediated excretion.