Potential Modulation of Polygoni Cuspidati Rhizoma et Radix on Breast Cancer Resistance Protein and Marked Alteration on Methotrexate Pharmacokinetics

<b>Background/Objectives</b>: Polygoni Cuspidati Rhizoma et Radix (PCRR) is an herb and a source of a resveratrol-containing dietary supplement. Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter involved in numerous drug-related pharmacokinetic interactions. This study used both in vivo and <i>in vitro</i> models to investigate the modulation effect of PCRR ingestion on BCRP. <b>Methods</b>: Three groups of rats were orally administered methotrexate (MTX), a probe substrate of BCRP, without and with PCRR at 1.0 g/kg and 2.0 g/kg in a parallel design, and the MTX pharmacokinetics were compared among three treatments. The modulation effects of PCRR and its serum metabolites (PCRRM) on BCRP were assayed by <i>in vitro</i> models. <b>Results</b>: PCRR at 1.0 g/kg and 2.0 g/kg significantly decreased the area under the serum level-time curve from 0 to 240 min (AUC_0-240) of MTX by 31% and 58%, respectively; 2.0 g/kg of PCRR markedly increased the area under the serum level-time curve from 240 to 2880 min (AUC_240-2880) and the mean residence time (MRT) of MTX by 39% and 74%, respectively. The results of <i>in vitro</i> assays indicated that PCRR enhanced the function of BCRP by 33~48%; on the contrary, PCRRM reduced the function of BCRP by 200~209%. <b>Conclusions</b>: PCRR activated BCRP, whereas PCRRM inhibited BCRP, thereby the coadministration of PCRR reduced both the absorption and excretion of MTX in rats. In clinical practice, the concurrent use of PCRR with critical BCRP substrate drugs should be avoided.