ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, which is the processed lateral roots of Aconitum Carmichaeli. Debx and is widely distributed over the southwest provinces of China, is recognised for its anti-inflammatory and analgesic effects. AIM OF THE STUDY: The pharmacokinetic properties of Fuzi are inadequately understood. Aconitine, the primary highly toxic ingredient of Fuzi, is well known as the target marker of Fuzi. The purpose of the present study is to investigate the pharmacokinetic behaviours of aconitine in vivo following single and multiple administrations of processed Fuzi extracts and to compare the pharmacokinetic characteristics of aconitine after administrations of pure aconitine or Fuzi extracts as well as compare the difference at single dose and multiple doses. The in vitro aconitine protein binding in plasma through equilibrium dialysis was also examined. METHODS: A high performance liquid chromatography (HPLC) method was developed for the determination of aconitine in Fuzi crude extracts and a fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed to investigate the pharmacokinetic behaviour of aconitine as the targeted marker of Fuzi. RESULTS: The absolute bioavailability (F %) after the administration of 0.5 mg/kg aconitine and Fuzi extract (0.118 mg/kg aconitine) in rat was 8.24±2.52% and 4.72±2.66%, respectively. Aconitine absorption was very fast at the t(max) 30.08±9.73 min for pure aconitine and 58.00±21.68 min for Fuzi extract administration. Aconitine was also eliminated rapidly with a short half-life (i.v., 80.98±6.40 min) and a low rate of protein bounding (23.9-31.9%). No significance was observed on all the pharmacokinetics parameters following the single and multiple doses of pure aconitine (ANOVA, p>0.05). However, the absorption of aconitine after multiple administrations of Fuzi extract was much faster than that of a single dose (t(max): 58.00±21.68 vs. 20.00±8.66 min, p<0.05), and the area under the plasma concentration-time curve (AUC) was higher than that of a single dose. CONCLUSIONS: The pharmacokinetic behaviour of processed Fuzi was determined in this paper. The aconitine has low bioavailability. No variation in the pharmacokinetic behaviours of pure aconitine was observed after single and multiple administrations. In contrast, multiple administrations of processed Fuzi extract could result in variations in its pharmacokinetic behaviour in AUC and t(max) indicating that multiple dose might increase the bioavailability of aconitine, which may result in its toxicity. In addition, aconitine has a low protein bounding (23.9-31.9%), resulting in its rapid elimination.
ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, which is the processed lateral roots of Aconitum Carmichaeli. Debx and is widely distributed over the southwest provinces of China, is recognised for its anti-inflammatory and analgesic effects. AIM OF THE STUDY: The pharmacokinetic properties of Fuzi are inadequately understood. Aconitine, the primary highly toxic ingredient of Fuzi, is well known as the target marker of Fuzi. The purpose of the present study is to investigate the pharmacokinetic behaviours of aconitine in vivo following single and multiple administrations of processed Fuzi extracts and to compare the pharmacokinetic characteristics of aconitine after administrations of pure aconitine or Fuzi extracts as well as compare the difference at single dose and multiple doses. The in vitro aconitine protein binding in plasma through equilibrium dialysis was also examined. METHODS: A high performance liquid chromatography (HPLC) method was developed for the determination of aconitine in Fuzi crude extracts and a fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed to investigate the pharmacokinetic behaviour of aconitine as the targeted marker of Fuzi. RESULTS: The absolute bioavailability (F %) after the administration of 0.5 mg/kg aconitine and Fuzi extract (0.118 mg/kg aconitine) in rat was 8.24±2.52% and 4.72±2.66%, respectively. Aconitine absorption was very fast at the t(max) 30.08±9.73 min for pure aconitine and 58.00±21.68 min for Fuzi extract administration. Aconitine was also eliminated rapidly with a short half-life (i.v., 80.98±6.40 min) and a low rate of protein bounding (23.9-31.9%). No significance was observed on all the pharmacokinetics parameters following the single and multiple doses of pure aconitine (ANOVA, p>0.05). However, the absorption of aconitine after multiple administrations of Fuzi extract was much faster than that of a single dose (t(max): 58.00±21.68 vs. 20.00±8.66 min, p<0.05), and the area under the plasma concentration-time curve (AUC) was higher than that of a single dose. CONCLUSIONS: The pharmacokinetic behaviour of processed Fuzi was determined in this paper. The aconitine has low bioavailability. No variation in the pharmacokinetic behaviours of pure aconitine was observed after single and multiple administrations. In contrast, multiple administrations of processed Fuzi extract could result in variations in its pharmacokinetic behaviour in AUC and t(max) indicating that multiple dose might increase the bioavailability of aconitine, which may result in its toxicity. In addition, aconitine has a low protein bounding (23.9-31.9%), resulting in its rapid elimination.
Authors: Yuqiao Zhang; Dali Tian; Yuyou Huang; Ling Li; Juan Mao; Juan Tian; Jinsong Ding Journal: Acta Pharm Sin B Date: 2016-06-11 Impact factor: 11.413