Absorption, distribution, metabolism experimental models

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

As described in several chapters of the present book [1,7], the application of pharmacokinetic (PK) and pharmacodynamic (PD) methods is widely accepted in the pharmaceutical industry. A PK model typically predicts the availability of a drug in the blood and interstitial spaces at different times after the drug has been administered. The model is used to determine characteristic parameters of the absorption, distribution, metabolism, and excretion processes from experimentally observed time courses, or the model follows the rates of formation and removal of various metabolites. PD models describe the effects of the drug (and its metabolites) as a function of time, again based on statistical fits to experimental results. 

An important feature of drug development is the estimation of pharmacokinetic parameters in animal models. Pharmacokinetics is the study of the time dependence and mechanism of absorption of a compound dosed into the body, its distribution throughout the fluids and other body tissues, the sequential metabolic transformations of the compound and its first-generation metabolites, and the elimination of the original compound and its metabolites (whence the common abbreviation ADME studies). The usual experimental raw data consist of concentrations of the test compound (and sometimes of its metabolites) in body tissues and body fluids (blood plasma, urine) as a function of time following a single dose. Extraction of quantitative parameters characterizing this behavior is determined by the theoretical model used to interpret the data. For example, if the dose is administered intravenously and the compound concentrations are measured in the blood, there will be an immediate drop of compound concentration with time as the compound is re-distributed, metabolized and excreted, but if an oral dose is used (as... 

In the specific case of lead metabolism, a number of models have been proposed and published over the years to rationalize the biological behaviour of lead in human subjects and experimental animals. The development and predictive utility of these models rest in large part on the considerable amount of empirical information available in the literature, relating to lead absorption, distribution, excretion, and retention in humans and test species. 

Model refinement and validation for both the chltnpyrifos and the diazinon PBPK/PD models wa.s accomplished by conducting a scries of in vivo pharmacokinetic and pharmacodynamic studies in the rat and by evaluating the capability of the model to accurately simulate in vivo data published in the literature. The experimental details are fully described in Timchalk et ai (2002b) and Poet et at. (2004). In brief, these studies involved an acute oral exposure to chlorpyrifos or diazinon and the blood time course of the parent compounds and metabolites was determined, as well as the time course for the cholinesterase inhibition in several tissues. Representative results and model simulations are presented in Fig. 12 and 13 for the pharmacokinetic and pharmacodynamic response in rats following comparable oral doses (50 and 100 mg/kg) of chlorpyrifos and diazinon, respectively, The overall response was fairly comparable for these two insecticides, and the models reasonably simulated both dosimetry and the dose-dependent cholinesterase inhibition. These results arc very consistent with a fairly rapid oral absorption for both insecticides and subsequent metabolism and distribution of the active oxon metabolites. Figure 14 illustrates the capability of the diazinon PBPK/PD model to simulate rodent dosimetry data from the open literature and the capability of the model to accommodate alternative exposure routes (Poet et ai, 2004). In these examples, the time course of diazinon in plasma and cholinesterase inhibition in tissues (i.e.. blood,... 

There are many other reported applications of GAs in related fields. Some, which may be of interest, include finding low-energy distributions of ions above a crystal surface optimizing parameters for allosteric regulation of enzymes in a model metabolic cycle minimizing the discrepancies between experimental and theoretical fluorescence/absorption spectra thin film analysis and parameter estimation for kenetic models. ... 

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