A Physiologically based Pharmacokinetic Model for Intravenous and Ingested Dimethylarsinic Acid in Mice

Abstract

A physiologically based pharmacokinetic (PBPK) model for the organoarsenical dimethylarsinic acid (DMA(V)) was developed in mice. The model was calibrated using tissue time course data from multiple tissues in mice administered DMA(V) intravenously. The final model structure was based on diffusion limitation kinetics. In general, PBPK models use the assumption of blood flow-limited transport into tissues. This assumption has historically worked for small lipophilic organic solvents. However, the conditions under which flow-limited kinetics occurs and how to distinguish when flow-limited versus diffusion-limited transport is more appropriate, have been rarely evaluated. One important goal of this modeling effort was to systematically evaluate descriptions of flow-limited compared with diffusion-limited tissue distribution for DMA(V), using the relatively extensive pharmacokinetic data available in mice. The diffusion-limited model consistently provided an improved fit over flow-limited simulations when compared with tissue time course iv experimental data. After model calibration, an independent data set obtained by oral gavage of DMA(V), was used to further test model structure. Sensitivity analysis of the two PBPK model structures showed the importance of early time course data collection, and the impact of diffusion for kidney time course data description. In summary, this modeling effort suggests the importance of availability of organ specific time course data sets necessary for the discernment of PBPK modeling structure, motivated by knowledge of biology, and providing necessary feedback between experimental design and biological modelers.

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology

“…For large molecular weight compounds such as the 150-kDa antibody considered here, extravasation from the vascular to interstitial space is the rate-limiting step for tissue uptake; therefore, AUC 7 is almost completely insensitive to the range of Q values evaluated for muscle and liver (37-416 μL/min/g), consistent with previous findings [16,17]. Although not evaluated here, one would expect small molecule tissue uptake to be sensitive to Q [58]. The sensitivity analyses discussed here and in previous works [16,17] are, strictly speaking, valid only for each respective model/parameter combination.…”

Relative Bioavailability and Bioaccessibility and Speciation of Arsenic in Contaminated Soils

“…Extant data on gastrointestinal absorption of ingested arsenicals facilitate use of the mouse as a test species in assays of soil As bioavailability (Hughes et al 2003, 2005, 2008). Although mice and humans differ in metabolism and disposition of arsenicals (Vahter 1999), similarities are sufficient to permit use of mouse data to create physiologically based pharmacokinetic models that can be scaled for humans (El-Masri and Kenyon 2008; Evans et al 2008; Gentry et al 2004a, 2004b; Hughes et al 1999). …”

Development and evaluation of a harmonized whole body physiologically based pharmacokinetic (PBPK) model for flutamide in rats and its extrapolation to humans

“…PBPK modeling have been used in inter-species, dose, duration and specific population extrapolations for the risk assessment (Andersen, 1995;Andersen and Dennison, 2001;Evans et al, 2008;Thiel et al, 2015). In this work, along with standard cross-species scaling approach Fig.…”