title: Paeoniflorin reduced acute toxicity of aconitine in rats is associated with the pharmacokinetic alteration of aconitine.
abstract: BACKGROUND
  To investigate the influence of paeoniflorin (major bioactive component of Paeonia lactiflora Pall.) on the pharmacokinetic behavior of aconitine (major toxic and bioactive component of Aconitum carmichaeli Debx.) and potential detoxifying effect of paeoniflorin on the acute toxicity of aconitine, which may provide in depth understanding to the toxicity reduction effect of Paeonia lactiflora to Aconitum carmichaeli.
  
  
  METHODS
  Ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC-MS/MS) was employed to determine the plasma content of aconitine. Aconitine was administrated by oral to SD rats at the dosage of 200 μg/kg with or without paeoniflorin given by intraperitoneal injection at the dosage of 20 mg/kg. Plasma samples were collected for determination and analysis of pharmacokinetic parameters of aconitine. The LD(50) of aconitine and acute animal death induced by aconitine were examined when aconitine was given alone or jointly with paeoniflorin in ICR mice.
  
  
  RESULTS
  A sensitive, accurate, precise, reliable and repeatable UHPLC-MS/MS method was successfully established for determination of the plasma content of aconitine in 12.5 μL plasma sample. The lower limit of quantification of aconitine was 0.01 ng/mL. Compared with the SD rats that were orally administrated with aconitine alone, the rats received aconitine and co-administrated with paeoniflorin by peritoneal injection showed a remarkably lower C(max) (5.69 ng/mL vs 9.66 ng/mL, P<0.05) and delayed T(max) (70 min vs 46 min, P<0.05), as well as a trend of reduction in AUC(0-t) (1082.75 ng-min/mL vs 1650.27 ng-min/mL, P=0.395). The LD(50) values of aconitine coadministered with 120 or 240 mg/kg of paeoniflorin were obviously increased to 2.30 and 2.15 mg/kg against 1.80 mg/kg of aconitine by oral administration alone. Mice treated with paeoniflorin (240 mg/kg) and aconitine (1.8 mg/kg) together revealed a significant decreased death rate than that received aconitine treatment alone (15% vs 50%, P<0.05).
  
  
  CONCLUSIONS
  The acute oral toxicity of aconitine in rats was significantly reduced by paeoniflorin; this might result from the alterations of pharmacokinetic behavior of aconitine in the animals by coadministration of paeoniflorin.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, Guangdong, PR China.
authors.forename: Yan Fang
authors.initials: YF
authors.lastname: Fan
authors.forename: Ying
authors.initials: Y
authors.lastname: Xie
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Hing Man
authors.initials: HM
authors.lastname: Ho
authors.forename: Yuen Fan
authors.initials: YF
authors.lastname: Wong
authors.forename: Zhong Qiu
authors.initials: ZQ
authors.lastname: Liu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
mesh_terms: D000157:Aconitine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D031841:Aconitum / Q000737:chemistry; D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D002138:Calibration; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000633:toxicity; D005960:Glucosides / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007928:Lethal Dose 50; D008297:Male; D008516:Medicine, Chinese Traditional; D008657:Metabolic Clearance Rate; D051379:Mice; D008813:Mice, Inbred ICR; D039821:Monoterpenes; D029596:Paeonia / Q000737:chemistry; D010946:Plants, Medicinal; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry / Q000592:standards; D006027:Glycosides
chemical_list: D000157:Aconitine; D001565:Benzoates; D001952:Bridged-Ring Compounds; D004365:Drugs, Chinese Herbal; D005960:Glucosides; D039821:Monoterpenes; C015423:peoniflorin; D006027:Glycosides