The effects of verapamil on the pharmacokinetics of curculigoside in rats.

Context: Clarifying the potential mechanism of the poor oral bioavailability of curculigoside would be helpful for for investigating pharmacological effects and clinical applications. Objective: To clarify the main mechanism for poor oral bioavailability. Materials and methods: First, the pharmacokinetics of curculigoside (20mg/kg) in rats with and without pretreatment with verapamil (10mg/kg) was determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of curculigoside were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems. Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 60.17 ng/mL to 93.66 ng/mL) and AUC(0-t) (from 289.57 to 764.02 ng.h/mL) of curculigoside. The Caco2 cell experiments indicated that the efflux ratio of curculigoside was 3.92 (P-appAB 6.43 +/- 0.57 x 10(-7)cm/s; P-appBA 2.52 +/- 0.37 x 10(-36)cm/s), P-gp might be involved in the transport of curculigoside, and verapamil could inhibit the efflux of curculigoside and increase the absorption of curculigoside significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly decrease the intrinsic clearance rate of curculigoside (from 38.8 to 23.6 mu L/min/mg protein). Discussion and conclusion: These results indicated that verapamil could significantly change the pharmacokinetic profiles of curculigoside 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 the poor oral absolute bioavailability of curculigoside.