The Effects of Verapamil on the Pharmacokinetics of Paeoniflorin in Rats

Paeoniflorin, a Chinese herbal medicine, has been widely used in clinical practice in China because of its numerous pharmacological activities. This study investigates the effects of verapamil on the pharmacokinetics of paeoniflorin in rats and clarify its potential mechanism. First, the pharmacokinetics of paeoniflorin (20 mg/kg) in rats with or without pretreatment with verapamil (10 mg/kg) were determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of paeoniflorin were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems. The results showed that verapamil could significantly increase the peak plasma concentration (from 137.68 +/- 12.48 to 185.25 +/- 21.01 ng/mL) and AUC(0-t) (from 990.35 +/- 110.25 to 1472.48 +/- 243.52 ng.h/mL) of paeoniflorin. The Caco-2 cell experiments indicated that the efflux ratio of paeoniflorin was 2.90 (P-appAB 6.35 +/- 0.52 x 10(-7) ; P-appBA 1.84 +/- 032 x 10(-6) cm/s), P-gp might be involved in the transport of paeoniflorin, and verapamil could inhibit the efflux of paeoniflorin and increase the absorption of paeoniflorin significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly increase the metabolic stability of paeoniflorin from 31.5 to 46.8 min. Those results indicated that verapamil could significantly change the pharmacokinetic profiles of paeoniflorin in rats, the poor absorption due to P-gp mediated efflux in intestine and high intrinsic clearance rate in rat liver may be the main reason for its poor oral absolute bioavailability of paeoniflorin.