Modeling Chemical Clearance - Metabolism and Excretion

Chemical reactivity can be a two-edged sword for toxicity. It can be beneficial if the parent chemical quickly reacts and degrades to either more benign or more easily cleared products. However, reactivity can be harmful if the reactions lead to damage to proteins or DNA. This is the case discussed here. One type of reactivity-mediated toxicity is skin sensitization caused when a low molecular weight compound penetrates into the epidermis and covalently reacts with an underlying protein. 

Once a chemical is in systemic circulation, the next concern is how rapidly it is cleared from the body. Under the assumption of steady-state exposure, the clearance rate drives the steady-state concentration in the blood and other tissues, which in turn will help determine what types of specific molecular activity can be expected. Chemicals are processed through the liver, where a variety of biotransformation reactions occur, for instance, making the chemical more water soluble or tagging it for active transport. The chemical can then be actively or passively partitioned for excretion based largely on the physicochemical properties of the parent compound and the resulting metabolites. Whole animal pharmacokinetic studies can be carried out to determine partitioning, metabolic fate, and routes and extent of excretion, but these studies are extremely laborious and expensive, and are often difficult to extrapolate to humans. To complement these studies, and in some cases to replace them, physiologically based pharmacokinetic (PBPK) models can be constructed [32, 33]. These are typically compartment-based models that are parameterized for particular 

The rate of disappearance of parent and fraction unbound can then be fed into a one-compartment PK model to produce individual or population-based estimates of the concentration at steady state (Css) that would result from a steady-state dose of 1 mg kg 1 per day of the given chemical. One can then compare the values of Css across a set of chemicals for which the exposure might be similar and make a preferential choice of the one with the lowest Css, all other factors being equal. 

Note that this equation applies to any in vitro assay, whether it measures direct molecular interaction or a more complex cellular phenotype. 

4-D would show activity at a lower dose of 0.017 mg kg-1 per day, and would be considered the less safe of the two relative to that pathway. 

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