The Research Of The Absorption, Distribution And Excretion Of TMT And The Transformation Of DMT In Rats

Objective: Discuss the metabolism of trimethyltin chloride (TMT) in rats, including the absorption, distribution, transformation and excretion. Prove the conversion from the harmfulless dimethyltin chloride (DMT) to the highly toxic TMT in rats. Provide a theoretical basis for poisoning risk assessment and clinical treatment of TMT.Methods: (1)Distribution in blood in vitro: 6 SD rats were blooded from the inferior vena cava after anesthesia. The same amount of TMT was added into the blank blood in each tube. The concentration of TMT in whole blood, plasma and red blood cell were measured after the different time of 0h, 10min, 0.5h, 1h, 2h and 4h in water bath, respectively.(2)Absorption, distribution and excretion test: 54 female and 54 male SD rats were divided into 18 groups at random. Group 1st was the control group and collected the blood from the orbital vein plexus after the intraperitoneal injection of saline immediately. the other 17 groups were given TMT 10mg/kg and collected the blood from the orbital vein plexus after the intraperitoneal injection at the different time of 10,20,30 min; 1,2,3,4,6,8 , 12,24 h; 3,6,9,12,28,90 d respectively .we also collected the rats'main organs detected the concentrations of TMT in blood and organs by GC-MS. 5 female and 5 male SD rats were given TMT 10 mg / kg orally. then we collected the urine of a total of 13 time periods of before exposure -12-0h and after exposure 1,2,3,6,9,12,18,28 , 40,55,70,90 d. The urine creatinine, urine PH value and the TMT content were determined. The toxicokinetic parameters were calculated using the pharmacokinetic software 3P87.(3)Transformation test: 10 female SD rats were given DMT 10 mg / kg, for 3 days continuously by intraperitoneal injection. The 24-hour urine was collected for 10 days continuously after administration by individual metabolic cages. The concentrations of TMT and DMT in urine were determined by GC-MS and corrected by urinary creatinine. The total urine excretion rate of DMT and the total conversion rate from DMT to TMT were calculated per animal per day. (4)acute toxicities and plasma potassium tests:rats and mice were treated with DMT in gavage (ig), by intraperitoneal injection (ip) and by intradermal injection (ii) respectively to measure the acute toxicities (LD50). Plasma potassium levels in rats were measured at 1 hour and on 1 day after treated with DMT (ip).Resulds: Methodology: To establish sensitive, reliable, specific detection methods of TMT and DMT in animals'tissues by GC-MS. The relationship between response signal (Y) and TMT concentration (X) was linear well in range of 0.259-25.9μg / g. The linear equation was Y = 4049.3X +45.312, R2 = 0.9996 and The lower limit of quantification was 0.1295μg / g. the within-run and between-run precisions were 1.65-6.72% and 7.81-19.41%,respectively.the relative recovery and extraction recovery were 84.32-104.02% and 91.46-101.91%,respectively. All these indicators and parameters were in line with the requirements of the toxicokinetics research.Distribution in the blood components in vitro: TMT entered into RBC quickly after espousing to TMT in vitro and the TMT concentration in RBC was about 2 times than the concentration in blood. The concentration of TMT in plasma was the least and about 1 / 200 of it in whole blood.Absorbtion: (1) TMT was absorbed rapidly in the rats'gastrointestinal tract: In blood the peak time was 1.78 h, peak concentration was 111.67μg/ml, half-absorbed period was 0.16h.In plasma peak time was 2.10 h, peak concentration was 0.99μg/ml, half-absorbed period was 0.21h. (2) TMT was cleared very slowly in rats: Blood elimination rate constant was1.98×10-3 / h and clearance rate was 1.77×10-4 L / kg / h, indicating that The TMT in only 0.177mL blood was cleared per hour. plasma elimination rate constant was 2.95×10-3 / h and clearance rate was 0.03 L / kg / h. (3) only a very small part of TMT distributed in the plasma after entering into the blood: the mean AUC area under the curve of blood was 56448.67μg/ml * h, while the plasma was only 337.21μg/ml * h, so the former was about 167 times then the latter. (4) TMT elimination speed in the plasma was faster: the blood elimination half-reduction period of TMT was 349.15h, about 15 days, while the plasma elimination half-reduction of the TMT was 234.69h, about 10 days. (5) TMT could reduce the serum potassium and increased the PH in urine.Distribution in tissues: (1) TMT absorbed quickly in the tissues, we could detect the presence of TMT in 10min group. The concentrations of TMT in 30min group were close to the peak, and 6h group were highest. (2) TMT was cleared very slowly in the tissues. The concentrations were reduced to only about half of the peak values until the 12d and the TMT could still be detected in 28d group. (3) TMT into rats, the concentrations were higher in the heart, liver, spleen and kidney, and the order from the higher to lower was spleen> liver > kidney> heart. The TMT in brain, muscle, fat, reproductive system and other tissues were lower.Elimination in urine: (1) TMT excreted slowly in urine and the urinary excretion were relatively constant every day: The concentration of TMT that corrected by creatinine was the highest on the 6th day and about the 1/8 peak value on the 28th day. The TMT could still be detected in urine on the 90th day. (2) TMT could lead to the PH rising of the rat urineThe conversion from DMT to TMT: the lower toxic DMT could transfer into the higher toxic TMT in rats and the conversion rate was about 0.80%±0.22% in urine.Acute toxicity of DMT: DMT is medium toxicity which could induce potassium decline temporarily.Conclusions: We basicly completed the metabolic research of TMT after a single oral administration in SD rats. A sensitive, reliable, specific quantitative detection method of TMT in animals'tissues by GC-MS was established and the detection methods of both TMT and DMT at the same time in urine samples were improved well. The acute toxicity of DMT and its effects on serum potassium were also researched. We demonstrated that DMT can be converted into TMT in rats and the conversion rate in urine was also obtained.