Effects of paeoniflorin‐6′‐O‐benzene sulfonate on the pharmacokinetics, excretion and tissue distribution of leflunomide in rats

Abstract Paeoniflorin‐6′‐O‐benzene sulfonate (CP‐25) is a novel ester derivative of paeoniflorin, which has been shown to have synergistic pharmacodynamic effects with leflunomide (LEF). To determine the effects of CP‐25 on the pharmacokinetics of LEF in rats, we developed a ultra‐high performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS)‐based method for the determination of levels of teriflunomide (TER, an active metabolite of LEF). This method was used to determine TER concentrations in the plasma, urine, faeces and bile; heart, liver, spleen, lung, kidney, intestinal, brain and synovial tissues; and peripheral blood mononuclear cells (PBMCs) of rats in the control (LEF [10 mg/kg]) and combined (CP‐25 [50 mg/kg × 7d] plus LEF [10 mg/kg]) groups. TER area under the curve [AUC], T max , mean residence time (MRT), t 1/2α and t 1/2β were significantly lower, and clearance (CL) was significantly higher in the combined group than in the control group. Oral CP‐25 administration in combination with LEF was found to promote TER excretion in urine, faeces and bile and to reduce its contents in most tissues and organs, especially in the liver, which may reduce LEF‐induced liver injury. CP‐25 also increased TER exposure in the synovium and its absorption by PBMCs, and this could explain the synergistic effects of CP‐25 and LEF.