Abstract
The liver is the central organ for detoxification of xenobiotics in the body. In pharmacokinetic modeling, hepatic metabolization capacity is typically quantified as hepatic clearance computed as degradation in well-stirred compartments. This is an accurate mechanistic description once a quasi-equilibrium between blood and surrounding tissue is established. However, this model structure cannot be used to simulate spatio-temporal distribution during the first instants after drug injection. In this paper, we introduce a new spatially resolved model to simulate first pass perfusion of compounds within the naive liver. The model is based on vascular structures obtained from computed tomography as well as physiologically based mass transfer descriptions obtained from pharmacokinetic modeling. The physiological architecture of hepatic tissue in our model is governed by both vascular geometry and the composition of the connecting hepatic tissue. In particular, we here consider locally distributed mass flow in liver tissue instead of considering well-stirred compartments. Experimentally, the model structure corresponds to an isolated perfused liver and provides an ideal platform to address first pass effects and questions of hepatic heterogeneity. The model was evaluated for three exemplary compounds covering key aspects of perfusion, distribution and metabolization within the liver. As pathophysiological states we considered the influence of steatosis and carbon tetrachloride-induced liver necrosis on total hepatic distribution and metabolic capacity. Notably, we found that our computational predictions are in qualitative agreement with previously published experimental data. The simulation results provide an unprecedented level of detail in compound concentration profiles during first pass perfusion, both spatio-temporally in liver tissue itself and temporally in the outflowing blood. We expect our model to be the foundation of further spatially resolved models of the liver in the future.
Highlights
The liver is the main site of metabolization and detoxification of xenobiotics in the body of mammals
To apply our model to pharmacological scenarios, we considered the distribution of three exemplary compounds covering typical aspects of drug distribution and metabolization: (1) the tracer carboxyfluorescein diacetate succinimidyl ester (CFDA SE), (2) the sedative midazolam, and (3) the antibiotic spiramycin
We used the CFDA SE model to verify that the overall mass balance is satisfied in the combined model
Summary
The liver is the main site of metabolization and detoxification of xenobiotics in the body of mammals. While renal clearance can be measured by urinary secretion, a quantification of liver detoxification capacity is difficult since the different physiological functions cannot be assessed directly. While hepatic turnover can be indirectly quantified with drugs following a known pharmacokinetic profile, the local, time-resolved distribution of compounds within the whole organ can generally not be analyzed even with distinguished measurement techniques. This holds in particular for the first pass of drug perfusion in a liver directly after drug administration, when hepatic tissue is exposed to a novel xenobiotic for the first time
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