Physiologically based pharmacokinetic (PBPK) modeling is a technique used for predicting the absorption, distribution, metabolism and excretion (ADME) of chemicals in humans and other animal species. In chemical/pesticide human health risk assessment, PBPK modeling is used to develop Data-Derived Extrapolation Factors for interspecies and intraspecies extrapolation. Intrinsic clearance (CLint) is one of the parameters used in PBPK modeling. In the present study, CLint values of bifenthrin (BIF), a pyrethroid insecticide, were determined in microsomes of juvenile and adult rats and humans. The study design included incubation of bifenthrin (up to 300 µM) in human (adult: &gt;18 yrs, pediatric: &lt; 5 yrs) and rat (adult: PND 90 days, juvenile: PND 15 days) liver microsomes (0.3 mg protein/ml) for 15 min. The metabolic clearance of bifenthrin was monitored via formation of the two major metabolites: 4’-hydroxy-bifenthrin, the primary oxidation product (4’-OH-BIF) and TFP acid, the primary hydrolytic product in the test systems. Michaelis-Menten graphs, Vmax and Kmwere obtained using GraphPad Prism® software. The CLint values of bifenthrin for 4’-OH-BIF formation in adult and young rat liver microsomes (RLM) were 4.42 and 1.05 μL/min/mg, respectively, while the CLint for TFP acid formation were 5.52 and 3.34 μL/min/mg in adult and young RLM, respectively. The CLint values of bifenthrin for 4’-OH-BIF formation in adult and young human liver microsomes (HLM) were 2.44 and 7.57 μL/min/mg, respectively. The corresponding values for TFP acid formation were 0.938 and 1.58 μL/min/mg. These data demonstrate that while bifenthrin metabolism is relatively inefficient in young rats compared to adults, the opposite is true for humans, where its in vitro hepatic clearance is higher in children than in adults. This difference in age dependent clearance of bifenthrin is similar to other xenobiotics that are primarily metabolized by CYP2C9/19.

Higer in vitro hepatic clearance of bifenthrin in children versus adults

254th National Meeting (2017)

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