Pharmacokinetic And Metabolic Evaluation Of Lappaconitine Hydrobromide

Lappaconitine is a diterpene alkaloid extracted from roots of Aconitum sinomontanum. It is Non-narcotic central nervous system analgesics, with strong analgesic action. Analgesic activities of lappaconitine were greater than those of indometacin and acetylsalicylic acid, but generally about 2 to 5 times less than those of morphine. Animal experiments showed that it hadn't teratogenic effect and it didn't cause cumulative intoxication. Otherwise, lappaconitine also has local anesthesia and anti-inflammatory effect.High sensitive and rapid method was to be developed for the pharmacokinetic and metabolic study of lappaconitine in mouse plasma and rat urine using liquid chromatography coupled to mass spectrometry (LC-MS/MS). A selective HPLC-UV method would be used for the excretion behavior study of lappaconitine in rat urine.Methods:The mice were intravenously injected with different dose of lappaconite hydrobromide. The plasma concentration of lappaconitine in mice were measured by HPLC-MS. The rats were oral administration with a dose of lappaconite hydrobromide at 12.0 mg/kg. The urine samples were measured by LC-MSn. HPLC-UV method was used for studying the excretion behavior of lappaconite.Resuluts:The method was linear over the concentration range of 3.0-2000.0 ng/ml. The lower limit of quantification was 3.0 ng/ml. Intra-and inter-day precisions (RSD) were both less than 9.9% and accuracy (RE) within±4.8%. After single intravenous injection of different dose of lappaconite hydrobromide, the main pharmacokinetic parameters were as follows:t1/2 were 0.48 h; MRT were 0.25 h; CL were 296 ml/min; Vz were 12.3 l/kg. The selective HPLC-UV method for the determination of lappaconitine in rat urine was developed. The method was linear over the concentration range of 0.20-20.0μg/ml. Eleven metabolites were found in rat urine, six of which were found firstly. Lappaconitine and its N-deacetylated metabolite (M7) were the two predominant metabolites determined in rat urine. The percentage of cumulative amount of the two predominant metabolites excreted in rat urine in dose was5.86% within 8h.Conclusion:The method herein described was successfully applied to the evaluation of pharmacokinetic profile of lappaconitine in mice. After single intravenous injection of lappaconite hydrobromide, results indicated that the pharmacokinetic profiles of lappaconite hydrobromide fit the linear dynamic feature over the dose range studied. The major metabolic pathways of lappaconitine in rat urine were hydroxylation, O-demethylationg, N-deacetylation metabolite and ester hydrolyzation.