| As a kind of halogenated hydrocarbon compound,2-Bromo-5-fluorobenzotrifluoride is a widely-used pharmaceutical intermediate and also an important intermediate of pesticide and liquid crystal material.For example,it is an intermediate of drugs such as bicaluamide,dicyclic dopamine D3 receptor antagonist and LSZ102.This compound belongs to 6.1 category of toxic substances.Any contact with eyes and skin or inhalation of it may cause serious irritation to eyes and skin,and stimulation to respiratory,resulting in skin allergy,central nervous system weakness,and even death in serious cases.With the ever-expanding application of 2-bromo-5-fluorobenzotrifluoride as an intermediate in drug synthesis,its market demand is also increasing.However,during the production process,its residual may become an impurity,which may endanger the safety and efficacy of this drug.Therefore,for this kind of intermediate with a large production,its chemical toxicology evaluation is very necessary to get the safety data related to its toxicity,while the metabolic kinetic test is an important part of the toxicology evaluation.In summary,this paper seeks to analyze the toxicokinetics of 2-bromo-5-fluorobenzotrifluoride in rats from the following aspects:1.Study on the basic kinetic characteristics of 2-bromo-5-fluorobenzotrifluoride in ratsA GC-MS method was established and verified for the determination of 2-bromo-5-fluorobenzotrifluoride in rat plasma.The plasma samples were extracted with toluene solution and centrifuged at high speed,and got the supernatant for analysis.The standard curve had a good linear relationship in the concentration range of 0.2～50 μg/m L,with the correlation coefficient r=0.999,and its extraction recovery rate of was stable between 85.9%～92.9%.All the methods were in accordance with the guiding principles of quantitative analysis of biological samples.Rats were given 200 mg/kg,500 mg/kg,and 1000 mg/kg drugs respectively via a single gavage together with a single intravenous injection of 20 mg/kg 2-bromo-5-fluorobenzotrifluoride.Use GC-MS to analyze the plasma samples before administration and at different time points after administration.Through the DAS 3.3.1 pharmacokinetic software,the main parameters of toxic absorption kinetic were obtained after fitting by the statistical distance method.The results showed that the rats were given2-bromo-5-fluorobenzotrifluoride by oral administration,Tmax of the three groups was 0.43 ± 0.30 h,4.40 ± 0.89 h and 7.33 ± 2.31 h respectively,indicating that Tmax was increased significantly with the increase of the dose;the t1/2 of was 4.17±2.22 h,5.21±2.50 h and 8.21±3.65 h,indicating that t1/2 also increased with the increase of the dose;the AUC(0-t)was63.80±9.92 μg/m L·h,164.11±59.80 μg/m L·h and 333.95± 17.98 μg/m L·h,indicating that AUC(0-t)was positively correlated with the dose of the drug;the Cmax was 15.97 ± 3.78 μg/m L·h,16.95 ± 8.83 μg/m L·h and μg/m L·h,indicating that the increase of Cmax was smaller between the range of200～500 mg/kg and bigger in the range between 500～1000 mg/kg,and it was also positively correlated with the dose;the absolute bioavailability of it in the three groups was 91.8%,94.4%,and 96.1%,respectively.The results showed that 2-bromo-5-fluorobenzotrifluoride was well-absorbed in rat body,and there was no saturation of absorption at a dose within 1000mg/kg.2.Study on the tissue distribution of 2-bromo-5-fluorobenzotrifluoride in ratsA GC-MS method was established and validated for the determination of 2-bromo-5-fluorobenzotrifluoride in rat tissues.The established method was used to study the distribution of it in blood and 9 tissues after oral administration of 1000 mg/kg to rats.The tissue samples were homogenized and extracted with toluene solution,centrifuged at high speed,and the upper organic phase was separated for analysis.The results showed that the concentration in each tissue has a good linearity in the range of0.2-50 μg/m L,r = 0.999;the range of extraction recovery rate of this drug was stable between 93.9% and 97.5%.Each method was in accordance with the validation guidelines for the quantitative analysis methods of biological samples.After rats were given 1000 mg/kg 2-bromo-5-fluorobenzotrifluoride via oral gavage,this compound was widely distributed in rat tissues.It was mainly distributed in fat and skin,followed by kidneys,intestines,liver and thyroid,but least in spleen,heart and testes.It is worth noting that at the same time point,the content of 2-bromo-5-fluorobenzotrifluoride in tissues was higher than that in plasma.The content of it in the heart,intestines and skin showed a tendency of first decrease and then increase.In other tissues,its content was consistent with the plasma,and they tended to gradually decrease over time.3.Study on the excretion of 2-bromo-5-fluorobenzotrifluoride in ratsA GC-MS method was established and verified for determining the concentration of 2-bromo-5-fluorobenzotrifluoride in rat urine,feces and bile.The excretion rates of 3 kinds of excreta after intragastric administration of 1 000 mg / kg 2-bromo-5-fluorobenzotrifluoride were studied.The concentration of this drug in the 3 kinds of excrement had good linearity in the range of 0.2～50 μg/m L,r = 0.999,and the extraction recovery rate was stable and greater than 89.0%.Each method was in accordance with the validation guidelines for the quantitative analysis methods of biological samples.After rats were orally exposed to 1000 mg/kg2-bromo-5-fluorobenzotrifluoride,the excretion rate of urine accumulation in 144 h was 0.039% ± 0.005%;the cumulative excretion rate of fecal accumulation in 144 h was 44.27% ± 32.32%;the cumulative excretion rate of bile accumulation in 144 h was 0.0443% ± 0.0135%.The results showed that after a single oral administration of 1000 mg/kg2-bromo-5-fluorobenzotrifluoride in rats,it was mainly excreted through feces,and only a small part of this drug was excreted through urine and bile. |
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