Methotrexate improves the anti-arthritic effects of Paeoniflorin-6'-O-benzene sulfonate by enhancing its pharmacokinetic properties in adjuvant-induced arthritis rats

Paeoniflorin-6'-O-benzene sulfonate (CP-25), is a novel derivative of paeoniflorin (Pae) with improved anti-arthritic effects. The aim of this study was to evaluate the therapeutic effects and pharmacokinetics of CP-25 when co-administered with MTX in adjuvant-induced arthritis (AA) rats. AA rats were randomly divided into 6 groups and treated as follows: TGP (50 mg/kg/day, ig), CP-25 (50 mg/kg/day, ig), MTX (0.5 mg/kg, 3 times/week, ig), TGP (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) and CP-25 (50 mg/kg/day, ig) + MTX (0.5 mg/kg, 3 times/week, ig) from days 14 - 35 after induction. Clinical, biochemical, and histological scores were used to assess the severity of arthritis while novel ultra-performance liquid chromatography mass spectrometry (UPLC-MS/MS) was used to detect plasma concentration of CP-25. Co-administration of CP-25 and MTX significantly reduced clinical signs of inflammation, suppressed the serum production of IL-17 compared to TGP (50 mg/kg/day, ig) and MTX (0.5 mg/kg, 3 times/week, ig). Pharmacokinetics studies showed increased AUC0-t, Cmax, and t1/2 of CP-25 while V/F and CL/F decreased when co-administered with MTX. We observed an increase concentration and longer exposure with decreased clearance of CP-25 when combined with MTX, that should be further explored for clinical RA therapy.