Toxicokinetic analysis

The simplest toxicokinetic analysis involves measurement of the plasma concentrations of a chemical at several time points after the administration of... 

Sampling Interval To be able to perform valid toxicokinetic analysis, it is not only necessary to properly collect samples of appropriate biological fluids, but also to collect a sufficient number of samples at the current intervals. Both of these variables are determined by the nature of the answers sought. Useful parameters in toxico-kinetic studies are Cmax, which is the peak plasma test compound concentration Tmax, which is the time at which the peak plasma test compound concentration occurs, Cmin, which is the plasma test compound concentration immediately before the next dose is administered AUC, which is the area under the plasma test compound concentration-time curve during a dosage interval, and t which is the half-life for the decline of test compound concentrations in plasma. The samples required to obtain these parameters are shown in Table 18.12. Cmin requires one blood sample immediately before a dose is given and provides information on accumulation. If there is no accumulation in plasma, the test compound may not be detected in this sample. 

Eyer F, Meischner V, Kiderlen D, et al. (2003) Human parathion poisoning. A toxicokinetic analysis. Toxicological Reviews 22(3) 143-163. 

Pharmacokinetics/toxicokinetics may be defined as the study of the dynamic movements of xenobiotics during their passage through the body and as such encompass the concept of disposition described previously (Figure 1). In simpler words, it tells us what the body does to foreign chemicals. To that end, pharmacokinetic/toxicokinetic analysis uses mathematical terms, or equations, to describe the time course of the absorption and disposition of xenobiotics in the body and proposes simplified representations (models) of the relationship between time and movements of xenobiotics. Once the information on the concentration of a chemical in biologically relevant parts of the body is provided by pharmacokinetic/toxicokinetic studies, it then usually becomes possible to better understand, interpret, and even predict the nature and the extent of the biological effects of xenobiotics. 

The purpose of this article is to introduce the reader to simple basic concepts and principles of pharmacokinetic/toxicokinetic analysis using both types of models - compartmental and physiologically based. 

As seen earlier, exposure conditions amenable to pharmacokinetic/toxicokinetic analysis are such that the rate of the biological processes (e.g., diffusion across membranes, biotransformation, excretion by glomerular filtration, etc.) is proportional to the concentration or amount of a xenobiotic in a given compartment such as blood. The rate is then said to be governed by first-order kinetics (see Figures 2 and 3). 

Pharmacokinetic/toxicokinetic analysis is a very important tool that can help toxicologists understand how the body handles foreign chemicals. With a good knowledge of the time course relationship between exposure to chemicals and their concentration in various tissues and organs, toxicologists are in a position to better interpret and predict the nature and extent of toxicity. 

Hobara T, Kobayashi H, Higashihara E. et al. 1982. [Experimental examinations and toxicokinetic analysis of the absorption and excretion of 1,1,1-trichloroethane by the lung]. Sangyo Igaku 24 599-607. (Japanese)... 

Methods of detection, metabolism, and pathophysiology of the brevetoxins, PbTx-2 and PbTx-3, are summarized. Infrared spectroscopy and innovative chromatographic techniques were examined as methods for detection and structural analysis. Toxicokinetic and metabolic studies for in vivo and in vitro systems demonstrated hepatic metabolism and biliary excretion. An in vivo model of brevetoxin intoxication was developed in conscious tethered rats. Intravenous administration of toxin resulted in a precipitous decrease in body temperature and respiratory rate, as well as signs suggesting central nervous system involvement. A polyclonal antiserum against the brevetoxin polyether backbone was prepared a radioimmunoassay was developed with a sub-nanogram detection limit. This antiserum, when administered prophylactically, protected rats against the toxic effects of brevetoxin. 

Tier III analysis Toxicokinetic/toxicodynamics. The role of ADME in designing safer chemicals... 

The multimedia model present in the 2 FUN tool was developed based on an extensive comparison and evaluation of some of the previously discussed multimedia models, such as CalTOX, Simplebox, XtraFOOD, etc. The multimedia model comprises several environmental modules, i.e. air, fresh water, soil/ground water, several crops and animal (cow and milk). It is used to simulate chemical distribution in the environmental modules, taking into account the manifold links between them. The PBPK models were developed to simulate the body burden of toxic chemicals throughout the entire human lifespan, integrating the evolution of the physiology and anatomy from childhood to advanced age. That model is based on a detailed description of the body anatomy and includes a substantial number of tissue compartments to enable detailed analysis of toxicokinetics for diverse chemicals that induce multiple effects in different target tissues. The key input parameters used in both models were given in the form of probability density function (PDF) to allow for the exhaustive probabilistic analysis and sensitivity analysis in terms of simulation outcomes [71]. 

Short-term non-invasive biomarkers for processes producing long-term lung damage-evaluation of the feasibility of candidate measurement systems. Toxicokinetic models have been developed to determine whether breath analysis of pentane and ethane can be used to estimate chronic lung damage from toxicants. 

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 major advantage of an in vitro system is that it represents a simplified system which allows the experimenter to address questions which cannot be tested in vivo. These systems can allow analysis of activation or metabolism at the single enzyme level. They can test proposed pathways of metabolism or activation. Such studies are not practical with in vivo systems. The major disadvantage is that in vitro systems are a simplified system and the results can be easily over-interpreted. In vitro systems cannot model the pharmacokinetics or toxicokinetics of xenobiotic exposure in vivo. In addition, there may be other, unappreciated enzymes or factors which influence metabolism/toxicity in vivo which are not present in the in vitro system. 

Therefore, the pharmacokinetic parameters, which can be derived from blood level measurements, are important aids to the interpretation of data from toxicological dose-response studies. The plasma level profile for a drug or other foreign compound is therefore a composite picture of the disposition of the compound, being the result of various dynamic processes. The processes of disposition can be considered in terms of "compartments." Thus, absorption of the foreign compound into the central compartment will be followed by distribution, possibly into one or more peripheral compartments, and removal from the central compartment by excretion and possibly metabolism (Fig. 3.23). A very simple situation might only consist of one, central compartment. Alternatively, there may be many compartments. For such multicompartmental analysis and more details of pharmacokinetics and toxicokinetics, see references in the section "Bibliography." The central compartment may be, but is not necessarily, identical with the blood. It is really the compartment with which the compound is in rapid equilibrium. The distribution to peripheral compartments is reversible, whereas the removal from the central compartment by metabolism and excretion is irreversible. 

Toxicokinetics studies are designed to measure the amount and rate of the absorption, distribution, metabolism, and excretion of a xenobiotic. These data are used to construct predictive mathematical models so that the distribution and excretion of other doses can be simulated. Such studies are carried out using radiolabeled compounds to facilitate measurement and total recovery of the administered dose. This can be done entirely in vivo by measuring levels in blood, expired air, feces, and urine these procedures can be done relatively noninvasively and continuously in the same animal. Tissue levels can be measured by sequential killing and analysis of organ levels. It is important to measure not only the compound administered but also its metabolites, because simple radioactivity counting does not differentiate among them. 

Although virtually no information is available regarding the toxicokinetics of acrolein in humans, analysis of the urine of individuals accidentally exposed to the chemical or living in polluted urban areas would provide valuable information on absorption and excretion rates if the exposure to acrolein was know. 

After a short period as assistant veterinarian in an animal hospital he joined the former Hoechst AG as Laboratory Head in 1992, performing various kinds of animal studies with radiolabeled isotopes in the life-science area of pharmaceutics, veterinarian medicine and crop science. During this time he completed his education as a specialist for Radiology. Following the break-up of the different parts of the company he became Section Head, responsible not only for carrying out animal studies but also for the analysis, evaluation and assessment of all kinds of pharmacokinetic and toxicokinetic animal studies. 

In a fashion similar to the discussion presented on organic chemicals, Baas et al. (2007) applied the 1-compartment model without TK interactions for the analysis of-time series survival data for the springtail Folsomia Candida exposed to binary mixtures of heavy metals. It must be stressed that no internal concentrations were measured in these experiments instead, the toxicokinetics parameters were solely determined from the survival pattern in time. In this case, the toxicity data were well described without assuming interactions, which stresses that even though we know that interactions on toxicokinetics can occur, this does not mean that they will significantly influence toxicity for every metal mixture in each organism. 

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