Simultaneous determination of paeoniflorin-6′-O-benzene sulfonate (CP-25) and its active paeoniflorin (Pae) metabolite in rat plasma using UPLC-MS/MS: an application for pharmacokinetic studies

Paeoniflorin (Pae), a water-soluble monoterpene glucoside, is the main effective component of total glucoside of paeony (TGP). Pae has a very low bioavailability (3.6%). The aim of this study was to investigate the effects of sex, food and disease status on the pharmacokinetics of paeoniflorin-6′-O-benzene sulfonate (acylated derivative of Pae, CP-25) and its primary metabolite (Pae, M1) after oral administration in the plasma of rats. A specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for rapid determination of CP-25 and Pae in rat plasma was developed and validated for the first time. The assay was validated in terms of selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. We found that CP-25 had a more extensive distribution in females than that in males, but no differences in M1 levels were found. Food intake could also increase the extent of absorption and decrease the rate of clearance for CP-25 and M1 after oral administration in rats. The disease status would decrease the absorption of CP-25 in rats. Comparing single-doing and multiple-dosing in an adjuvant arthritis (AA) model, the absorption of CP-25 and M1 improved with increasing dosage. Furthermore, during the period of multiple-dosing, CP-25 exhibited a better anti-inflammatory effect in AA rats and no obvious side effects occurred during the dosing period. Our findings provide the basis, and some guidelines, for further studies into the clinical application of CP-25.