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2-溴-4-氟乙酰苯胺在雄性大鼠体内的毒物动力学行为

朱狄峰 童振轩 洪雅雯 陈超 赵剑岚 平丽

朱狄峰, 童振轩, 洪雅雯, 陈超, 赵剑岚, 平丽. 2-溴-4-氟乙酰苯胺在雄性大鼠体内的毒物动力学行为[J]. 农药学学报, 2021, 23(2): 357-365. doi: 10.16801/j.issn.1008-7303.2021.0057
引用本文: 朱狄峰, 童振轩, 洪雅雯, 陈超, 赵剑岚, 平丽. 2-溴-4-氟乙酰苯胺在雄性大鼠体内的毒物动力学行为[J]. 农药学学报, 2021, 23(2): 357-365. doi: 10.16801/j.issn.1008-7303.2021.0057
Difeng ZHU, Zhenxuan TONG, Yanwen HONG, Chao CHEN, Jianlan ZHAO, Li PING. Toxicokinetics of 2-bromo-4-fluoroacetanilide in male SD rat[J]. Chinese Journal of Pesticide Science, 2021, 23(2): 357-365. doi: 10.16801/j.issn.1008-7303.2021.0057
Citation: Difeng ZHU, Zhenxuan TONG, Yanwen HONG, Chao CHEN, Jianlan ZHAO, Li PING. Toxicokinetics of 2-bromo-4-fluoroacetanilide in male SD rat[J]. Chinese Journal of Pesticide Science, 2021, 23(2): 357-365. doi: 10.16801/j.issn.1008-7303.2021.0057

2-溴-4-氟乙酰苯胺在雄性大鼠体内的毒物动力学行为

doi: 10.16801/j.issn.1008-7303.2021.0057
基金项目: 浙江省自然科学基金项目 (LY17H310004);浙江省科技计划项目 (2017C33139)
详细信息
    作者简介:

    朱狄峰,男,助理研究员,主要从事药物毒理与毒代动力学研究,E­mail:zhudf@zju.edu.cn

    通讯作者:

    平丽,通信作者 (Author for correspondence),女,实验师,主要从事药物毒理与毒代动力学研究,E­mail:pingli552@zju.edu.cn

  • 中图分类号: S481.1;TQ450.26

Toxicokinetics of 2-bromo-4-fluoroacetanilide in male SD rat

  • 摘要: 2-溴-4-氟乙酰苯胺 (2-bromo-4-fluoroacetanilide,BFAA) 是多种N-苯基酰胺类化合物合成的中间体,也是合成农药时的主要杂质。本研究建立了一种快速、特异的超高效液相色谱-串联质谱 (UPLC-MS/MS) 检测方法,用于测定大鼠血浆、组织、尿液和粪便中的2-溴-4-氟乙酰苯胺含量,以获得该化合物的吸收、分布及排泄等动力学信息。大鼠经不同剂量的2-溴-4-氟乙酰苯胺灌胃和静脉注射染毒处理后,取血浆及不同组织样品,经蛋白质沉淀法处理后采用所建立的UPLC-MS/MS方法测定,分别计算2-溴-4-氟乙酰苯胺的血药浓度达峰时间 (tmax)、血药峰浓度 (Cmax) 和药-时曲线下面积 (AUC(0-t)) 等血浆毒物动力学参数和绝对生物利用度 (F),考察了药物在组织中的分布和经尿液、粪便排泄的特征。血浆毒物动力学研究表明:大鼠灌胃后药物可被迅速吸收,给予200、500和1000 mg/kg的2-溴-4-氟乙酰苯胺后,其 tmax 值分别为 (0.2 ± 0.1)、(0.4 ± 0.2) 和 (0.5 ± 0.3) h;Cmax 和 AUC(0-t) 值分别为 (32.4±5.0)、(45.2±1.8)、(38.5±3.2) mg/L和(121.2±40.9)、(393.3±51.1)、(321.9±38.0) (mg/L)·h;F 值在 34.1%~83.3% 之间。其血浆药-时曲线具有双峰现象,推测可能存在重吸收或肠-肝循环。组织分布研究表明:2-溴-4-氟乙酰苯胺在组织中分布较广,且主要分布在小肠、胃和脂肪中;此外在脑和睾丸中发现了少量该化合物,表明其可以穿过血脑屏障和睾丸屏障;24 h后大部分组织中已检测不到该化合物,表明其总体不存在蓄积现象;靶向分配系数均小于1.0,提示2-溴-4-氟乙酰苯胺对组织无明显的选择性。排泄研究结果表明:2-溴-4-氟乙酰苯胺经尿液和粪便的排泄主要发生在0~48 h内,分别占总排泄量的93%和92%;经尿液和粪便的总排泄量为 (80.6 ± 29.8) μg,仅占总染毒量的 (0.03 ± 0.01) %,提示经尿液和粪便的排泄并非2-溴-4-氟乙酰苯胺母体化合物主要的体内消除途径。
  • 1  2-溴-4-氟乙酰苯胺化学结构式

    1.  The structural formula of BFAA

    图  1  大鼠血浆样品典型质谱图

    A. 空白血浆;B. 添加 2-溴-4-氟乙酰苯胺 (40 μg/mL) 和内标氯雷他定 (6.7 ng/mL) 的血浆; C. 1 000 mg/kg剂量2-溴-4-氟乙酰苯胺灌胃染毒1 h后血浆样本中添加内标氯雷他定 (6.7 ng/mL) 。 A1、B1、C1:2-溴-4-氟乙酰苯胺;A2、B2、C2:内标氯雷他定。

    Figure  1.  Mass spectrogram of the plasma samples

    A. Blank plasma sample; B. Plasma sample with BFAA and IS loratadine; C. Plasma sample in 1 h after administration spiked with IS loratadine. A1, B1, C1: 2-Bromo-4-fluoroacetanilide; A2, B2, C2: IS loratadine.

    图  2  灌胃和静脉注射染毒后大鼠血浆中2-溴-4-氟乙酰苯胺的药-时曲线

    Figure  2.  The concentration-time curve of BFAA in rat plasma after administration

    图  3  灌胃和静脉注射染毒后大鼠血浆中2-溴-4-氟乙酰苯胺的毒代动力学参数与剂量的关系

    A. 血药峰浓度Cmax-剂量关系;B. 药-时曲线下面积AUC(0-t) -剂量关系;C. 表观分布容积V-剂量关系;D. 绝对生物利用度F-剂量关系。

    Figure  3.  Relationship between toxicokinetic parameters of BFAA and dose in rat plasma after administration

    A. Cmax-dose relationship; B. AUC(0-t) -dose relationship; C. Apparent volume of distribution V-dose relationship; D. Absolute bioavailability F-dose relationship.

    表  1  2-溴-4-氟乙酰苯胺在大鼠血浆中的毒代动力学参数 (mean ± SD, n = 5)

    Table  1.   Toxicokinetics parameters of BFAA in rat plasma (mean ± SD, n = 5)

    毒代动力学参数
    Toxicokinetics parameters
    灌胃
    Intragastric administration (i.g.)
    静脉注射
    Intravenous injection
    (i.v.) 20 mg/kg
    1000 mg/kg500 mg/kg200 mg/kg
    血药浓度达峰时间 tmax/h 0.5 ± 0.3 0.4 ± 0.2 0.2 ± 0.1 0.1 ± 0
    半衰期 t1/2/h 4.4 ± 1.8 7.5 ± 1.8 3.3 ± 0.2 5.9 ± 1.4
    血药峰浓度 Cmax/(mg/L) 38.5 ± 3.2 45.2 ± 1.8 32.4 ± 5.0 17.9 ± 1.7
    药-时曲线下面积 AUC(0-t)/((mg/L)·h) 321.9 ± 38.0 393.3 ± 51.1 121.2 ± 40.9 18.9 ± 9.3
    药-时曲线下面积 AUC(0-∞)/((mg/L)·h) 322.3 ± 37.8 397.6 ± 49.8 121.2 ± 40.9 18.9 ± 9.3
    曲线下面积比 R_AUC(t-∞)/% 99.9 ± 0.2 98.9 ± 1.4 100 ± 0 100 ± 0
    平均驻留时间 tmr(0-t)/h 12.4 ± 2.2 12.6 ± 0.9 4.4 ± 0.6 2.1 ± 1.7
    平均驻留时间 tmr(0-∞)/h 12.4 ± 2.2 13.3 ± 0.5 4.4 ± 0.6 2.1 ± 1.7
    平均驻留时间方差 VRT(0-t)/h2 91.2 ± 11.1 107.9 ± 12.0 13.0 ± 0.8 12.7 ± 23.2
    平均驻留时间方差 VRT(0-∞)/h2 93.6 ± 12.2 127.8 ± 46.2 13.1 ± 0.7 13.9 ± 23.9
    表观分布容积 V/(L/kg) 4.0 ± 1.9 13.2 ± 3.9 42. 8 ± 12.6 11.0 ± 5.0
    清除率 CL/((L/h)/kg) 0.6 ± 0.1 1.3 ± 0.2 8.8 ± 2.3 1.2 ± 0.4
    绝对生物利用度 F/% 34.1 83.3 64.2
    下载: 导出CSV

    表  2  不同染毒时间下大鼠各组织中2-溴-4-氟乙酰苯胺的含量 (mean ± SD, n = 5)

    Table  2.   Distribution of BFAA in rat tissues after administration (mean ± SD, n = 5)

    样本 Sample2-溴-4-氟乙酰苯胺含量
    Content of BFAA/(mg/kg)
    组织中药-时曲线下面积
    AUC(0-∞)/((mg/L)·h)
    靶向分配系数*
    Target distribution coefficient,TDC *
    0.5 h2 h8 h24 h
    心脏 Heart 100.8 ± 49.8 32.0 ± 7.0 15.4 ± 6.6 97.4 ± 17.5 0.3
    肝脏 Liver 2.8 ± 2.1 0.6 ± 0.2 0.2 ± 0.2 1.9 ± 1.0 0.006
    脾脏 Spleen 41.0 ± 11.1 18.5 ± 6.7 11.9 ± 1.7 60.4 ± 7.7 0.2
    肺 Lungs 2.7 ± 0.3 1.1 ± 0.3 0.3 ± 0.3 2.6 ± 0.9 0.008
    肾脏 Kidneys 9.8 ± 2.6 6.4 ± 2.5 18.6 ± 8.2 0.4 ± 0.9 62.2 ± 27.9 0.02
    脂肪 Fat 137.7 ± 47.3 50.7 ± 34.0 26.5 ± 6.3 0.3 ± 0.5 155.8 ± 38.0 0.5
    肌肉 Muscle 29.5 ± 3.5 14.8 ± 2.4 7.5 ± 1.7 41.9 ± 6.3 0.1
    脑 Brain 7.3 ± 1.3 4.0 ± 0.6 1.5 ± 0.7 9.8 ± 1.5 0.03
    睾丸 Testis 2.7 ± 0.5 0.9 ± 0.3 1.5 ± 0.3 0.005
    胃 Stomach 223.5 ± 42.3 12.5 ± 14.3 15.5 ± 8.6 0.6 ± 0.5 112.4 ± 13.6 0.3
    小肠 Intestine 309.8 ± 39.5 65.8 ± 11.2 11.5 ± 6.2 1.1 ± 0.8 174.5 ± 22.7 0.5
    注:* 靶向分配系数:组织中药-时曲线下面积/血浆中药-时曲线下面积。Note: * Target distribution coefficient (TDC) : AUC(0-∞) of tissue/AUC(0-∞) of plasma.
    下载: 导出CSV

    表  3  不同时间段大鼠尿液和粪便中2-溴-4-氟乙酰苯胺的排泄量 (mean ± SD,n = 5)

    Table  3.   Excretion of BFAA in rat urine and feces after administration during different time periods (mean ± SD,n = 5)

    排泄途径
    Excretion pathway
    排泄量
    Excretion amount/μg
    0~12 h12~24 h24~48 h48~72 h72~96 h96~120 h
    尿液 Urine 0.5 ± 0.7 2.8 ± 2.8 8.5 ± 6.4 0.5 ± 0.6 0.3 ± 0.3 0.1 ± 0.1
    粪便 Feces 11.6 ± 7.1 20.6 ± 13.3 30.6 ± 18.8 5.1 ± 2.2
    下载: 导出CSV

    表  4  大鼠尿液和粪便中2-溴-4-氟乙酰苯胺的累积排泄量及排泄率 (mean ± SD,n = 5)

    Table  4.   Amount and rate of cumulative excretion of BFAA in rat urine and feces (mean ± SD, n = 5)

    排泄途径
    Excretion pathway
    累积排泄量
    Amount of analyte/μg
    排泄率*
    Excretion rate,RE*/%
    累积总排泄量
    Cumulative excretion/μg
    累积总排泄率
    Cumulative excretion rate/%
    尿液 Urine12.8 ± 6.90.005 ± 0.00380.6 ± 29.80.030 ± 0.009
    粪便 Feces67.9 ± 33.20.025 ± 0.013
    注:*排泄率:累积排泄量/染毒量。Note: * Rate of excretion (RE) : cumulative excretion/total dose.
    下载: 导出CSV
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  • 收稿日期:  2020-06-10
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