Plasma protein binding, metabolism, reaction phenotyping and toxicokinetic studies of fenarimol after oral and intravenous administration in rats

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 AUC_0–∞ 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 (AUC_0–∞ 8270.53 ± 1798.59 h*ng/mL).

Keywords:

• Fenarimol
• toxicokinetics
• plasma protein binding
• metabolism
• non-linear kinetics
• reaction phenotyping

Acknowledgments

The authors wish to thank The Director, CSIR-Indian Institute of Toxicology Research (IITR), for providing facilities and infrastructure for the study. The authors are grateful to Science and Engineering Research Board (SERB), New Delhi, India for the support in the form of research grant (GAP 306) to carry out this research work. Authors Ashish Kumar Sonker and Manisha Bhateria are thankful to University Grant Commission (UGC) and Council of Scientific and Innovative Research (CSIR), respectively, for providing fellowship. CSIR-IITR communication number for this manuscript is 3604.

Disclosure statement

No potential conflict of interest was reported by the author(s).