Physiologically based pharmacokinetic modeling of nanoparticles in rodents

A variety of nanoparticles are under development for medicine, energy, food and cosmetics. Both organic and inorganic nanoparticles are playing an increased role in industrial and medical applications. However, little is known about their distribution and effects on the human body, and as a result concerns exist about potential health risks and safety problems. The long-term aim of this research is to quantify the distribution characteristics of nanoparticles and explore how the physicochemical properties of nanoparticles influence their distribution. A physiologically based pharmacokinetic (PBPK) model was successfully developed to describe the pharmacokinetics and biodistribution of nanoparticles in various tissues and blood of the body. A PBPK model based on permeability-limited distribution from the vasculature to tissue spaces was compared with the PBPK model based on flow-limited distribution using literature values for distribution of nanoparticles. In general, the blood-flow limited model is not accurate enough to explain the complete biodistribution of nanoparticles, whereas the permeability-flow limited model provides a more faithful simulation. We also applied a novel formulation of the PBPK model, in which blood plasma kinetics are decoupled from tissue kinetics, and compared the description to those of traditional, coupled PBPK models. Our model parameterization suggested that the decoupled model method without elimination based on permeability-flow limited model accurately predicted the trends of nanoparticles concentration in both tissue and blood. This could indicate that partition coefficients of tissues combining with blood flow to tissue might have a great influence on the biodistribution of nanoparticles. This work provides a foundation for more accurate PBPK correlation of nanoparticle biodistribution that should be of utility both in the emerging area of nanotoxicology and in the preclinical drug development of nanomedicines.M.S.Includes bibliographical referencesby Xiaowan L