Wuzhi capsule increased systemic exposure to methotrexate by inhibiting the expression of OAT1/3 and P-gp

Background: Methotrexate (MTX) is an important anticancer agent and immunosuppressant with a narrow therapeutic window. Wuzhi capsule (WZC) is an extract of Schisandra which is widely used to treat liver diseases. Co-administration of MTX and WZC is common in the clinical setting, but research on the interaction between WZC and MTX is limited. This study aimed to investigate the effects of WZC on the pharmacokinetics of MTX in rats and to explore the role of membrane transport proteins OAT1/3 and P-gp in the interaction of these drugs. Methods: Plasma MTX concentration was detected by ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS), and the messenger RNA (mRNA) and protein expression of OAT1/3 and P-gp was evaluated by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting analyses, respectively. Results: The study results revealed that co-administration of WZC decreased the CLz/F and V-z/F of MTX, increased the C-max and area under the curve [(AUC)(0-24) (h)] of MTX, and inhibited OAT1/3 expression in the kidney and P-gp expression in the small intestine. Conclusions: The findings suggested that there is a drug interaction between WZC and MTX and that OAT1/3 in the kidney and P-gp in the small intestine may be the main targets mediating the drug interaction, and attention should be paid when they are used in combination.

Automated summary

The study showed that co-administration of WZC reduced the clearance and volume distribution of MTX, increased the peak concentration and area under the curve of MTX, while inhibiting the expression of OAT1/3 in the kidney and P-gp in the small intestine. These findings suggest that there is a drug interaction between WZC and MTX, with OAT1/3 and P-gp playing key roles in mediating this interaction.