The Effects of Rheum palmatum L. on the Pharmacokinetic of Major Diterpene Alkaloids of Aconitum carmichaelii Debx. in Rats.

Abstract

Aconitum carmichaelii Debx. (Fuzi) is usually compatible with Rheum palmatum L. (Dahuang) in clinic. The study is conducted to investigate the influence of Dahuang on the pharmacokinetics of Fuzi. Twelve rats were randomly divided into two groups. Fuzi group was orally administered a single dose of 38.4mg/kg total alkaloids from Fuzi, and Fuzi-Dahuang group was given 38.4mg/kg total alkaloids from Fuzi and 76.8mg/kg Dahuang anthraquinones at the same time. The plasma concentrations of aconitine (AC), mesaconitine (MC), and hypaconitine (HC), benzoylaconine (BAC), benzoylmesaconine (BMC), benzoylhypaconine (BHC), and aconine (ACN) were determined by ultra-performance liquid chromatography-quadrupole time of flight mass spectrometry method. The pharmacokinetic parameters were calculated including maximum plasma concentration (C max), area under the plasma concentration-time curve in all time-points (AUClast), apparent volume of distribution (V z/F), apparent plasma clearance (CL/F), elimination half-life (T 1/2), and time to achieve maximum concentration (T max). AUClast of diester diterpene alkaloids (DDAs) were 58.20, 169.78, 278.48ng·h/mL for AC, MC, and HC in Fuzi-Dahuang group which were remarkably lower than that in Fuzi group (71.62, 183.13, 410.59ng·h/mL for AC, MC, HC). CL/F was significantly increased from 173.88 to 218.85mL/h for AC, 433.22 to 800.21mL/h for MC, 1150.61 to 1307.30mL/h for HC after combination. However, with the significantly increased C max, AUClast of monoester diterpene alkaloids (MDAs) and amine diterpenoid alkaloids (ADAs) were 152.42, 1238.95, 287.96, 123.33ng·h/mL for BAC, BHC, BMC, ACN in Fuzi-Dahuang group which were remarkably higher than that in Fuzi group (54.47, 1105.48, 200.75, 86.48 ng·h/mL for BAC, BHC, BMC, ACN). At the same time, CL/F was significantly decreased from 1030.15 to 607.09, 3594.06 to 1437.54, 1441.23 to 1310.14, and 391.30 to 239.50mL/h for each one after combination. Fuzi diterpene alkaloids pharmacokinetics was greatly influenced by Dahuang which may account for the compatibility mechanism of effect-enhancing and toxicity-reducing.