Pharmacokinetic models general

LeungH. 1993. Physiologically-based pharmacokinetic modeling. General and applied toxicology. 

LeungH. 1993. Physiologically-based pharmacokinetic modeling. General and applied toxicology. Vol. I. Ballantine B, Marro T, Turner T, eds. New York, NY Stockton Press, 153-164. 

Reaction rate parameters required for the distributed pharmacokinetic model generally come from independent experimental data. One source is the analysis of rates of metabolism of cells grown in culture. However, the parameters from this source are potentially subject to considerable artifact, since cofactors and cellular interactions may be absent in vitro that are present in vivo. Published enzyme activities are a second source, but these are even more subject to artifact. A third source is previous compartmental analysis of a tissue dosed uniformly by intravenous infusion. If a compartment in such a study can be closely identified with the organ or tissue later considered in distributed pharmacokinetic analysis, then its compartmental clearance constant can often be used to derive the required metabolic rate constant. 

Pharmacokinetic Model—A set of equations that can be used to describe the time course of a parent chemical or metabolite in an animal system. There are two types of pharmacokinetic models data-based and physiologically-based. A data-based model divides the animal system into a series of compartments which, in general, do not represent real, identifiable anatomic regions of the body whereby the physiologically-based model compartments represent real anatomic regions of the body. 

Thus far we have only considered relatively simple linear pharmacokinetic models. A general solution for the case of n compartments can be derived from the matrix K of coefficients of the linear differential equations ... 

Analysis of Data. Data from all metabolism and pharmacokinetic studies should be analyzed with the same pharmacokinetic model and results should be expressed in the same units. Concentration units are acceptable if the organ or sample size is reported, but percent of dose/organ is usually a more meaningfiil unit. In general, all samples should be analyzed for metabolites that cumulatively represent more than 1% of the dose. 

A specific example showing the application of these principles within a development program for an ER dosage form is shown in Figures 3-5. A generalized pharmacokinetic model that can be used to support prototype selection is shown in... 

A generalized pharmacokinetic model that can be used to support prototype selection is shown below. 

Levitt, D.G., PKQuest a general physiologically based pharmacokinetic model — introduction and application to propranolol, BMC Clin. Pharmacol, 1, 5, 2002. 

Many laboratory animal models have been used to describe the toxicity and pharmacology of chloroform. By far, the most commonly used laboratory animal species are the rat and mouse models. Generally, the pharmacokinetic and toxicokinetic data gathered from rats and mice compare favorably with the limited information available from human studies. PBPK models have been developed using pharmacokinetic and toxicokinetic data for use in risk assessment work for the human. The models are discussed in depth in Section 2.3.5. As mentioned previously, male mice have a sex-related tendency to develop severe renal disease when exposed to chloroform, particularly by the inhalation and oral exposure routes. This effect appears to be species-related as well, since experiments in rabbits and guinea pigs found no sex-related differences in renal toxicity. 

Pharmacokinetic models are used as tools to extrapolate from the results obtained in studies with experimental animals to predict effects in human populations that generally are exposed at lower environmental exposure levels compared to the generally higher exposure levels used in animal experiments. In such models, target tissue doses in different animal species under a variety of exposure conditions are predicted, using computer simulation. 

In fact, physiologically based pharmacokinetic models are similar to environmental fate models. In both cases we divide a complicated system into simpler compartments, estimate the rate of transfer between the compartments, and estimate the rate of transformation within each compartment. The obvious difference is that environmental systems are inherently much more complex because they have more routes of entry, more compartments, more variables (each with a greater range of values), and a lack of control over these variables for systematic study. The discussion that follows is a general overview of the transport and transformation of toxicants in the environment in the context of developing qualitative and quantitative models of these processes. 

Styrene Urinary metabolites Use of worker urinary metabolite-exposure information to develop pharmacokinetic model applicable to general public Appendix B... 

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