Folium Sennae Increased the Bioavailability of Methotrexate through Modulation on MRP 2 and BCRP

Abstract

Folium Sennae (FS), a popular laxative (Senna), contains polyphenolic anthranoids, whose conjugation metabolites are probable modulators of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). We suspected that the combined use of FS might alter the pharmacokinetics of various medicines transported by MRPs or BCRP. This study investigated the effect of FS on the pharmacokinetics of methotrexate (MTX), an anticancer drug and a probe substrate of MRPs/BCRP. Rats were orally administered MTX alone and with two dosage regimens of FS in a parallel design. The results show that 5.0 g/kg of FS significantly increased the AUC0–2880, AUC720–2880 and MRT of MTX by 45%, 102% and 42%, and the seventh dose of 2.5 g/kg of FS significantly enhanced the AUC720–2880 and MRT by 78% and 42%, respectively. Mechanism studies indicated that the metabolites of FS (FSM) inhibited MRP 2 and BCRP. In conclusion, the combined use of FS increased the systemic exposure and MRT of MTX through inhibition on MRP 2 and BCRP.

Case report: Hepatotoxicity and nephrotoxicity induced by methotrexate in a paediatric patient, what is the role of precision medicine in 2023?

“…The OATP1B1 gene is polymorphic, the most described variant being c.521T>C (rs4149056), for which the minor C allele is associated with reduced transport in vitro and reduced elimination of certain drugs in vivo ( Ramsey et al, 2014 ). BCRP, an ABC family transporter, is involved in the transport of various xenobiotics, including MTX ( Breedveld et al, 2004 ; Yu et al, 2021 ). It is most highly expressed in the brain, small intestine, cervix and uterus ( Fohner et al, 2017 ).…”