Physiologically based pharmacokinetic modeling of zinc oxide nanoparticles and zinc nitrate in mice

Zinc oxide nanoparticles (ZnO NPs) have been widely used in consumer products, therapeutic agents, and drug delivery systems. However, the fate and behavior of ZnO NPs in living organisms are not well described. The purpose of this study was to develop a physiologically based pharmacokinetic model to describe the dynamic interactions of (65)ZnO NPs in mice. We estimated key physicochemical parameters of partition coefficients and excretion or elimination rates, based on our previously published data quantifying the biodistributions of 10 nm and 71 nm (65)ZnO NPs and zinc nitrate ((65)Zn(NO3)2) in various mice tissues. The time-dependent partition coefficients and excretion or elimination rates were used to construct our physiologically based pharmacokinetic model. In general, tissue partition coefficients of (65)ZnO NPs were greater than those of (65)Zn(NO3)2, particularly the lung partition coefficient of 10 nm (65)ZnO NPs. Sensitivity analysis revealed that 71 nm (65)ZnO NPs and (65)Zn(NO3)2 were sensitive to excretion and elimination rates in the liver and gastrointestinal tract. Although the partition coefficient of the brain was relative low, it increased time-dependently for (65)ZnO NPs and (65)Zn(NO3)2. The simulation of (65)Zn(NO3)2 was well fitted with the experimental data. However, replacing partition coefficients of (65)ZnO NPs with those of (65)Zn(NO3)2 after day 7 greatly improved the fitness of simulation, suggesting that ZnO NPs might decompose to zinc ion after day 7. In this study, we successfully established a potentially predictive dynamic model for slowly decomposed NPs. More caution is suggested for exposure to (65)ZnO NPs <10 nm because those small (65)ZnO NPs tend to accumulate in the body for a relatively longer time than 71 nm (65)ZnO NPs and (65)Zn(NO3)2 do.