Yan Li1,2,3, Yun-Xia Li1,2,3, Meng-Jie Zhao1,2,3, An Yuan1,2,3, Xiao-Hong Gong1,2,3, Meng-Jun Zhao1,2,3, Cheng Peng4,5,6. 1. Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, People's Republic of China. 2. The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Chengdu, People's Republic of China. 3. State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, People's Republic of China. 4. Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, People's Republic of China. pengchengsub@126.com. 5. The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, Chengdu, People's Republic of China. pengchengsub@126.com. 6. State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 611137, People's Republic of China. pengchengsub@126.com.
Abstract
BACKGROUND AND OBJECTIVES: 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. METHODS: Twelve rats were randomly divided into two groups. Fuzi group was orally administered a single dose of 38.4 mg/kg total alkaloids from Fuzi, and Fuzi-Dahuang group was given 38.4 mg/kg total alkaloids from Fuzi and 76.8 mg/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). RESULTS: AUClast of diester diterpene alkaloids (DDAs) were 58.20, 169.78, 278.48 ng·h/mL for AC, MC, and HC in Fuzi-Dahuang group which were remarkably lower than that in Fuzi group (71.62, 183.13, 410.59 ng·h/mL for AC, MC, HC). CL/F was significantly increased from 173.88 to 218.85 mL/h for AC, 433.22 to 800.21 mL/h for MC, 1150.61 to 1307.30 mL/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, 123.33 ng·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 239.50 mL/h for each one after combination. CONCLUSIONS: Fuzi diterpene alkaloids pharmacokinetics was greatly influenced by Dahuang which may account for the compatibility mechanism of effect-enhancing and toxicity-reducing.
BACKGROUND AND OBJECTIVES: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. METHODS: Twelve rats were randomly divided into two groups. Fuzi group was orally administered a single dose of 38.4 mg/kg total alkaloids from Fuzi, and Fuzi-Dahuang group was given 38.4 mg/kg total alkaloids from Fuzi and 76.8 mg/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). RESULTS: AUClast of diesterditerpene alkaloids (DDAs) were 58.20, 169.78, 278.48 ng·h/mL for AC, MC, and HC in Fuzi-Dahuang group which were remarkably lower than that in Fuzi group (71.62, 183.13, 410.59 ng·h/mL for AC, MC, HC). CL/F was significantly increased from 173.88 to 218.85 mL/h for AC, 433.22 to 800.21 mL/h for MC, 1150.61 to 1307.30 mL/h for HC after combination. However, with the significantly increased C max, AUClast of monoester diterpene alkaloids (MDAs) and aminediterpenoid alkaloids (ADAs) were 152.42, 1238.95, 287.96, 123.33 ng·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 239.50 mL/h for each one after combination. CONCLUSIONS: Fuzi diterpene alkaloids pharmacokinetics was greatly influenced by Dahuang which may account for the compatibility mechanism of effect-enhancing and toxicity-reducing.