Determination of enzymatic kinetics of metabolism of dimethoate and omethoate in rats and humans

Abstract

1. Dimethoate is an organophosphate insecticide. The objective of this work was to determine the enzymatic kinetics of metabolism of dimethoate and its active metabolite omethoate in rats and humans and obtain key input parameters for physiologically based pharmacokinetic (PBPK) model.

2. First, the intrinsic clearance of dimethoate expressed as formation rate of omethoate was determined to be ∼42-fold lower in human liver microsomes (HLM) (0.39 µL/min/mg) than in rat liver microsomes (RLM) (16.6 µL/min/mg) by an LC/MS/MS method. Next, dimethoate clearance in liver microsomes was determined using parent depletion and total [¹⁴C]-metabolite formation methods. Results from both approaches showed slower clearance of dimethoate in HLM (1.1–3.3 µL/min/mg) than in RLM (12.7–17.4 µL/min/mg).

3. Investigation of in vitro enzymatic kinetics of omethoate demonstrated that the intrinsic clearance rates for omethoate in adult and juvenile RLM and HLM were similar. No significant turnover of dimethoate was apparent in rat cytosol or plasma. In contrast, degradation of omethoate in human plasma was slightly higher than in rat plasma.

4. Finally, toxicokinetics of dimethoate were determined in adult and juvenile rats. In both age groups, following oral dosing, absorption of dimethoate was rapid with formation of significant amounts of omethoate.

Keywords:

• Dimethoate
• omethoate
• in vitro metabolism
• ¹⁴C-dimethoate
• formation kinetics

Acknowledgment

Technical assistance provided by Jamie Boulet at Product Safety Labs (PSL), Dayton, NJ in conducting the in-life phase of the juvenile rat PK study is acknowledged.

Disclosure statement

The work presented in this paper on dimethoate was sponsored by FMC Corporation. The authors GN, AC, and PW are employees of FMC. RR serves as a consultant though a consulting company, Exponent (USA). The authors KK, LS are employees of Frontage Labs, a Contract Research Organisation where the in vitro and in vivo studies were performed.