St. John's wort significantly increased the systemic exposure and toxicity of methotrexate in rats

St. John's wort (SJW, Hypericum perforatum) is one of the popular nutraceuticals for treating depression. Methotrexate (MTX) is an immunosuppressant with narrow therapeutic window. This study investigated the effect of SJW on MTX pharmacokinetics in rats.Rats were orally given MTX alone and coadministered with 300 and 150 mg/kg of SJW, and 25 mg/kg of diclofenac, respectively. Blood was withdrawn at specific time points and serum MTX concentrations were assayed by a specific monoclonal fluorescence polarization immunoassay method.The results showed that 300 mg/kg of SJW significantly increased the AUC0−t and Cmax of MTX by 163% and 60%, respectively, and 150 mg/kg of SJW significantly increased the AUC0−t of MTX by 55%. In addition, diclofenac enhanced the Cmax of MTX by 110%. The mortality of rats treated with SJW was higher than that of controls.In conclusion, coadministration of SJW significantly increased the systemic exposure and toxicity of MTX. The combined use of MTX with SJW would need to be with caution.

► St. John's wort significantly increased the AUC0−t and Cmax of methotrexate.
► Coadministration of St. John's wort increased the exposure and toxicity of methotrexate.
► The combined use of methotrexate with St. John's wort will need to be with caution.