Toxicokinetics definition

If sufficient data are available, substance-specific PBPK models should always be given preference over the use of general scaling factors. However, PBPK models were considered not to replace all of the sub-factors in the interspecies comparison and should, by definition, only include toxicokinetic differences. A further extrapolation factor for toxicodynamic differences between the species needs to be discussed. 

Knowledge of the pKa value is crucial for analyzing both lipophilicity and solubility of ionizable compounds, as discussed above. Ionization equilibria also affect several toxicokinetic parameters, such as intestinal absorption, membrane permeability, protein binding, and metabolic transformations. Therefore, much research has been invested in developing both experimental and computational tools for pKa determination. Experimentally, two high-throughput methods exist spectral gradient analysis and capillary electrophoresis. However, the most definitive methods are still... 

The merit of this definition is that it distinguishes factors controlling the toxicokinetics of the substance (i.e., the rates of uptake, elimination, transformation, and internal distribution) from environmental factors (external to the organism) that control the amount of chemical that can be absorbed by the organism through a specific route of uptake. 

Exposure. The major data insufficiency with respect to biomarkers is the lack of quantitative factors that can be measured either in-life or postmortem, and that are uniquely indicative of white phosphorus poisoning. This deficiency is related to the lack of definitive information regarding white phosphorus toxicokinetics. Because little is known about the fate of white phosphorus in the body, there are no substance-quantity or substance-presence tests that are currently available that indicate white phosphorus intoxication. 

Based in this information difference between the NOEL and human exposure or the risk at a given exposure is determined. Humans may be exposed to chemicals in the air, water, food, or on the skin. From the concentrations of a chemical in these different compartments the external daily exposure is estimated. The response to the chemical depends upon duration and route of exposure, the toxicokinetics of the chemical, the dose-response relationship and the susceptibility of the individual. Thus, the precise definition of the terms hazard, exposure, and risk is essential to understand toxicological evaluations (details on data requirements and procedures for risk assessment are given subsequently). 

There is evidence that the only volatile compound of Otto Fuel II, propylene glycol dinitrate, is absorbed following exposure. Also, there is evidence for dermal or oral absorption from toxicity studies but no definitive toxicokinetic work has been done. 

A recommended approach for conducting toxicokinetic studies generally involves three steps. Step 1 is a preliminary study, which uses a minimum number of animals to estimate the range of blood/tissue concentrations, the required quantitation limit for the analytical method, and the optimal sampling times for the definitive toxicokinetic studies. Step 2 is the definitive study and generates blood and/or tissue concentration data for calculating the toxicokinetic parameters. Step 3 is the toxicokinetic study conducted in conjunction with the toxicology study to determine the internal dose and the effects of age and continuous exposure on kinetic parameters. 

Once a compound is selected for development, further studies are performed in animals and man to support the safety assessment and ensure that optimum dosing regimens are selected. Definitive in vivo PK and toxicokinetic studies are performed but also more detailed in vitro studies, particularly for the assessment of drug-drug interactions. ADME/PK support is continued throughout development (pre-clinical and phases I-IV) and a summary list of the main activities is shown in Table 4. 

Definition. Toxicokinetics is the movement and disposition of toxicants in the organism. 

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