A Liver-Centric Multiscale Modeling Framework for Xenobiotics

Abstract

We describe a multi-scale, liver-centric in silico modeling framework for acetaminophen pharmacology and metabolism. We focus on a computational model to characterize whole body uptake and clearance, liver transport and phase I and phase II metabolism. We do this by incorporating sub-models that span three scales; Physiologically Based Pharmacokinetic (PBPK) modeling of acetaminophen uptake and distribution at the whole body level, cell and blood flow modeling at the tissue/organ level and metabolism at the sub-cellular level. We have used standard modeling modalities at each of the three scales. In particular, we have used the Systems Biology Markup Language (SBML) to create both the whole-body and sub-cellular scales. Our modeling approach allows us to run the individual sub-models separately and allows us to easily exchange models at a particular scale without the need to extensively rework the sub-models at other scales. In addition, the use of SBML greatly facilitates the inclusion of biological annotations directly in the model code. The model was calibrated using human in vivo data for acetaminophen and its sulfate and glucuronate metabolites. We then carried out extensive parameter sensitivity studies including the pairwise interaction of parameters. We also simulated population variation of exposure and sensitivity to acetaminophen. Our modeling framework can be extended to the prediction of liver toxicity following acetaminophen overdose, or used as a general purpose pharmacokinetic model for xenobiotics.

A computational model for hepatotoxicity by coupling drug transport and acetaminophen metabolism equations

“…The main limitation of the coupled model is that, in the absence of concrete data from in vivo or in vitro experiments, some parameters have to be estimated. For example, the parameters k S , b S , d S , k 450 , k N , and k PSH in system have been chosen to produce physiologically realistic results, which were determined via parameter sensitivity analysis in Chalhoub et al Likewise, the reaction rate of CYP450 in zone 3 is modeled as being 1.3 times higher than that in zones 1 and 2, yet in Sluka et al, the concentration of CYP450 is treated as linearly increasing from the peri‐PT region to the peri‐CV region. This linear gradient would also induce a higher turnover of NAPQI in the peri‐CV region, leading to zonal hepatotoxicity.…”

“…Hence, an in silico model may be utilized to gain insights into the phenomena of hepatotoxicity. Previous mathematical models consider the spatial distribution of CYP450 only . Recently, our group has simulated the interplay of the spatial distributions of glucuronidation, sulfation, and oxidation enzymes on hepatotoxicity .…”

“…Previous mathematical models consider the spatial distribution of CYP450 only. 6,7 Recently, our group has simulated the interplay of the spatial distributions of glucuronidation, sulfation, and oxidation enzymes on hepatotoxicity. 8 We coupled an intracellular APAP metabolism model 9 consisting of a system of ordinary differential equations (ODEs) with a spatial-temporal sinusoid model and solved the system using the finite element method.…”

On computational approaches of liver lobule function and perfusion simulation

“…These sinusoids are described using a tube model with blood flow from the portal to central vein located in the center of the hexagonal shape of liver lobules. In contrast to Sluka et al, [12] they depict blood with the Einstein relation, that links the diffusion constant with the boundary conditions of one particle, assuming blood as a liquid with a low Reynolds number. Additionally, they also produce a zonation in metabolic processes based on the concentration cytochromes.…”

“…Sluka et al [12] have developed a multiscale model for detoxification processes in the human liver. Regarding all scales of the liver from metabolism on the subscale to a whole-body level, they describe the uptake and clearance of the drug acetaminophen.…”