Study On The Absorption, Distribution And Elimination Of Aconitum Alkaloids

Object:To study the absorption(A),distribution(D),and elimination(E) after iv. aconitine,mesaconitine and hypaconitine,respectively,and po.Aconitum alkaloid; discuss the toxic mechanism of the herbs of genus Aconitum in family of Ranunculaceae.Methods and Results1 MethodsWe successfully established the method of HPLC-MS-MS to detect aconitine mesaconitine and hypaconitine in biological samples including plasma,bile,urine and organs.The method(HPLC-MS-MS) is simple and efficient with excellent accuracy, precision,reproducibility and low detection limit.It can offer biological analysis in all calibration curves.We carried organ distribution after po aconitum alkaloid; metabolites after iv aconitine,mesaconitine and hypaconitine;elimination after iv. aconitine,mesaconitine,hypaconitine by the method.2 The study of toxicokineties after po aconitum alkaloidPo aconitum alkaloid in a single dose,the toxicokinetic parameters were estimated by the 3p97 program(designed by Chinese Pharmacological Society).According to the compartment model judgment principle,we chose the most suitable compartment model.Aconitine was a two compartment Model after po.The major toxicokinetic parameters are as follow.T_1/2alpha=3.326±1.564min,T_1/2beta=886.609±242.136min, t_1/2Ka=2.5192±0.846min,AUC=86557.852±9462.485(ng/ml)×min,T_(peak)=6.989 ±1.546min,CL(s)=0.000004±0.000001mg/kg/min/(ng/ml),C(max)=83.5489±10.4591ng/ml.Mesaconitine was a two compartment Model after po.The major toxicokinetic parameters are as follow.T_1/2alpha=15.4989±4.8712min,t_1/2Ka=3.618±1.254min,T_1/2beta =1255.8081±684.891min,T_peak=15.782±7.541min,C_max=202.983±30.781ng/ml,AUC =297212.38±74641.91(ng/ml)×min,CL(s)=0.000013±0.000009mg/kg/min/(ng/ml). Hypaconitine was a two compartment Model after po.The major toxicokinetic parameters are as follow.T_1/2alpha=125.482±51.654min,T_1/2beta=1007.7575±349.4852 min,t_1/2Ka=1.8541±1.4648min,AUC=241205.797±9146.841(ng/ml)×min,T_peak= 16.7646±5.4783min,CL(s)=0.000005±0.000002mg/kg/min/(ng/ml),C_max=164.3022±20.8914ng/ml.3 the study of organ distribution after po aconitum alkaloidWe found that aconitine,mesaconitine and hypaconitine were distributed in SD rats organs widely after multiple po aconitum alkaloid.Aconitine:samples of heart,liver,spleen,lung and kidney were all detected aconitine. The distribution of aconitine was in a descending order of lung,liver,heart,kidney, spleen.Samples of brain were also detected aconitine.Mesaconitine:samples of heart,liver,spleen,lung and kidney were all detected mesaco:aitine.The distribution of mesaconitine was a descending order of liver,lung, kidney,spleen and heart.In all brain and samples,we detected mesaconitine,but it was not enough to quantitate.Hypaconitine:samples of heart,liver,spleen,lung and kidney were all detected mesaconitine.The distribution of mesaconitine was a descending order of liver,lung, kidney,spleen and heart.We detected hypaconitine in all brain samples.But it was not enough to quantitate.In addition,because of individual variation,we found the content of same aconitum alkaloid had some difference in the same organ with different rat.4 the study of elimination after iv aconitine,mesaconitine and hypaconitine.We collected bile and urine to prepare samples after iv aconitine,mesaconitine and hypaconitine.In urine,the average elimination quantity of aconitine, mesaconitine,and hypaconitine after 24h iv the drugs were2.756±0.262/μg, 2.515±0.337μg,2.507±0.203μg,respectively.The ratio of elimination in the first 24h were 32.83±2.39%,29.94±3.45%,15.36±1.29%,respectively.In bile,we did not find aconitine,mesaconitine,and hypaconitine in all samples.It hinted us the drugs density were very insignificance.Conclusions:The research of organ distribution indicated that the aconitum alkaloid kept a high level in lung and liver.According to the study of aconitum alkaloid biotransformation and elimination,we basically understood aconitum alkaloid metabolic process and the rule of elimination in vivo.