Effects of Paeoniflorin-6'-O-benzene sulfonate on the pharmacokinetics, excretion, and tissue distribution of leflunomide in rats.

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 an 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, feces, 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 AUC, Tmax , MRT, t1/2α , and t1/2β were significantly lower and 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, feces, 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.