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Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats.
Xenobiotica ( IF 1.8 ) Pub Date : 2020-07-27 , DOI: 10.1080/00498254.2020.1796170
Kajal Karsauliya 1, 2 , Ashish Kumar Sonker 1, 3 , Manisha Bhateria 1 , Isha Taneja 4 , Anshuman Srivastava 1 , Manu Sharma 2 , Sheelendra Pratap Singh 1, 3, 5
Affiliation  

Abstract

  1. Fenarimol (FNL), an organic chlorinated fungicide, is widely used in agriculture for protection from fungal spores and fungi. Despite being an endocrine disruptor, no toxicokinetic data is reported for this fungicide.

  2. In the present work, we determined the plasma protein binding, metabolic pathways and toxicokinetics of FNL in rats.

  3. In vitro binding of FNL to rat and human plasma proteins was ∼90%, suggesting that FNL is a highly protein bound fungicide. The predicted in vivo hepatic clearance of FNL in rats and humans was estimated to be 36.71 and 14.39 mL/min/kg, respectively, indicating it to be an intermediate clearance compound. Reaction phenotyping assay showed that CYP3A4 mainly contributed to the overall metabolism of FNL.

  4. The oral toxicokinetic study of FNL in rats at no observed adverse effect level dose (1 mg/kg) showed maximum plasma concentration (C max) of 33.97 ± 4.45 ng/mL at 1 h (T max). The AUC0–∞ obtained was 180.18 ± 17.76 h*ng/mL, whereas, the t 1/2 was ∼4.74 h. Following intravenous administration, FNL displayed a clearance of 42.48 mL/min/kg which was close to the predicted in vivo hepatic clearance. The absolute oral bioavailability of FNL at 1 mg/kg dose in rats was 45.25%. FNL at 10 mg/kg oral dose exhibited non-linear toxicokinetics with greater than dose-proportional increase in the systemic exposure (AUC0–∞ 8270.53 ± 1798.59 h*ng/mL).



中文翻译:

口服和静脉内给药后在大鼠中的血浆蛋白结合,代谢,反应表型和芬太尼的毒性动力学研究。

摘要

  1. 苯那莫尔(FNL)是一种有机氯化杀菌剂,已广泛用于农业领域,以保护其免受真菌孢子和真菌的侵害。尽管是一种内分泌干扰物,但尚无该杀菌剂的毒代动力学数据报道。

  2. 在目前的工作中,我们确定了大鼠FNL的血浆蛋白结合,代谢途径和毒代动力学。

  3. FNL与大鼠和人血浆蛋白的体外结合率为〜90%,这表明FNL是一种高度蛋白结合的杀菌剂。预测在体内在大鼠和人类的FNL肝清除率估计为36.71和14.39毫升/分钟/公斤,分别指示它是一个中间的间隙化合物。反应表型分析表明CYP3A4主要参与了FNL的整体代谢。

  4. 在未观察到不良反应水平剂量(1 mg / kg)的大鼠中,对FNL进行的口服毒代动力学研究表明,在1 h(T max)时,最大血浆浓度(C max)为33.97±4.45 ng / mL 。所述AUC 0-∞获得的是180.18±17.76 H *毫微克/毫升,而,该1/2是~4.74小时。静脉内给药后,FNL的清除率为42.48 mL / min / kg,接近于体内预测肝脏清除率。在大鼠中1 mg / kg剂量的FNL绝对口服生物利用度为45.25%。口服剂量为10 mg / kg的FNL表现出非线性的毒代动力学,其全身暴露大于剂量比例的增加(AUC0 - ∞8270.53±1798.59 h * ng / mL)。

更新日期:2020-07-27
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