Résumé
AIM: To explore the effects of inflammatory conditions on the pharmacokinetics of methotrexate (MTX) and its related mechanisms. METHODS: The model of adjuvant induced arthritis (AIA) was established. The expression of organic anion transporter 3 (OAT3) in kidney was detected by immunohistochemistry, Western blotting and QPCR. The plasma concentration of MTX was detected by LC-MS/MS, and the pharmacokinetics of MTX after different administration time were compared by isolated rat kidney perfusion, kidney slices, in vitro cell uptake and transport experiments. RESULTS: The expression of OAT3 was significantly increased in the kidneys of AIA rats by immunohistochemistry, Western blotting and QPCR. At the same time, the concentration of MTX was detected by the optimized LC-MS/MS. The results showed that the uptake of MTX in the kidney slices of AIA rats was significantly increased, and Pro could reduce the excretion of MTX by inhibiting OAT3. Furthermore, it was demonstrated in vitro that inflammatory pathology can promote renal excretion of MTX by increasing the expression and functional activity of OAT3.CONCLUSION: Under inflammatory pathological conditions, it can increase the expression of OAT3 in the kidney, enhance its functional activity, accelerate the uptake of MTX by the kidney, and promote the excretion of MTX.
Résumé
Aim To investigate the effect of green tea polyphenols(GTP)on serum level of uric acid in potas-sium oxonate (PO)-induced hyperuricemic mice,and explore the potential mechanism.Methods PO and GTP were intragastricly administered to mice for seven consecutive days.Uric acid level in serum was exam-ined.Meanwhile,activity and expressions of xanthine oxidase(XOD)in liver were tested.In additon,ex-pressions of urate transporters including urate-anion transporter (URAT ) 1 , organic anion transporter (OAT)1 and 3 in kidney were analyzed.Results GTP significantly decreased the serum level of uric acid in PO-induced hyperuricemic mice.At the same time, GTP markedly reduced the activity and expression of XOD in liver of hyperuricemic mice.Finally,GTP markedly reduced the expression of URAT1 ,OAT1 and OAT3 in kidney of hyperuricemic mice.Conclusion GTP has the effect of lowering uric acid in PO-induced hyperuricemic mice through both decreasing the uric acid production and increasing uric acid excretion.