Toward a general physiologically-based pharmacokinetic model for intravenously injected nanoparticles

Abstract

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NPdependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Impact of dose and surface features on plasmatic and liver concentrations of biodegradable polymeric nanocapsules

“…The lower percentage of NC uptake by the liver observed in our experiments with increasing PLA and PLA-PEG NC polymeric doses suggests some degree of saturation of the MPS uptake pathways. Higher depletion of blood opsonins or complement consumption would possibly result in a decrease in the liver uptake of PLA NC compared to PLA-PEG NC as a function of an increase in the administered dose, as estimated for similar polymeric nanocarriers (Carlander et al, 2016). However, in the present study, no significant differences in liver uptake between both formulations were observed (p>0.05).…”

Biokinetics of nanomaterials: The role of biopersistence

“…The model was optimized by best fit to intravenous rat experimental data obtained with polyethylene glycolylated polyacrylamide (PAA-PEG) NMs (Li et al 2014). Carlander et al (2016) have slightly modified this model for simultaneous predictions of the following NMs: PAA-PEG, uncoated PAA, gold and TiO 2 NMs. These NMs were selected since sufficient experimental biokinetic data for optimization are available.…”

“…Further, the simulations demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NM-type included blood:tissue partition coefficients and the rate constant for phagocytic uptake (Carlander et al 2016). Since only four types of NMs with several differences in characteristics were used, the relationship between these characteristics and the NM-dependent model parameters could not be elucidated and more experimental data are required.…”

In vivo biodistribution and physiologically based pharmacokinetic modeling of inhaled fresh and aged cerium oxide nanoparticles in rats

“…M t,cap [μg per g] – PCs uptake capacity for nanoparticles per organ t weight, which is determined as the PCs number per organ weight (nanoparticle type independent) multiplied by the maximum uptake capacity in individual PCs (the same for all organs except the spleen) [35]. …”