PHARMACO-KINETICS OF COMBINED TOXICITY AFTER ADMINISTRATION OF ACONITINE AND TETRODOTOXIN IN MICE

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In this study, pharmaco-kinetic factors of combined toxicity after administration of aconitine (ACO) and tetrodotoxin (TTX) in mice were evaluated. A liquid chromatography - electrospray ionization - mass spectrometry (LC-ESI-MS) using the column - switching technique was performed on serum samples from ICR mice injected intraperitoneally with TTX (10 μg/kg), ACO (0.3 mg/kg) and the mixture of TTX and ACO (TTX 15 μg/kg, ACO 0.3 mg/kg). A column switching technique was developed to analyze TTX and Aconitum alkaloids and their metabolites without pretreatment of the serum, directly injected into a precolumn. Combination of a multimode column with reversed phases and cation exchange for TTX, and use of a multimode column with reversed phases and a hydrophobic polymer column for Aconitum alkaloids and their metabolites provided successful separation and MS determination in ESI positive mode. Mortality and surviving time after administration of TTX, ACO and the mixture of TTX and ACO were examined. TTX group and ACO group had low mortality and long surviving time, compared with the group treated with the mixture of TTX and ACO (TTX+ACO group). The serum concentrations of TTX were 0.9, 0.8, 2.4, 1.4, 0.7 ng/mL at 5, 15, 30, 45, 60 min in TTX group. The serum concentrations of ACO in ACO group showed higher levels compared with those in TTX+ACO group. But the serum concentrations of benzoylaconine, the main metabolite of aconitine, in ACO group showed lower levels compared with those in TTX+ACO group. The present findings have led to the suggestion that the metabolism of aconitine would have changed under the influence of TTX in mice.