Pharmacokinetic models physiologically-based model

Blakey GE, Nestorov lA, Arundel PA, Aarons LJ, Rowland M. Quantitative structure-pharmacokinetics relationships I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat. J Pharmacokinet Biopharm 1997 Jun 25(3) 277-312. Erratum in J Pharmacokinet Biopharm 1998 Feb 26(l) 131. 

Parrott, N Paquereau, N Coassolo, P Lave, Th. An evaluation of the utility of physiologically based models of pharmacokinetics in early drug discovery. f Pharm. Sci. 2005, 94, 2327-2343. 

FUN tool is a new integrated software based on a multimedia model, physiologically based pharmacokinetic (PBPK) models and associated databases. The tool is a dynamic integrated model and is capable of assessing the human exposure to chemical substances via multiple exposure pathways and the potential health risks (Fig. 9) [70]. 2-FUN tool has been developed in the framework of the European project called 2-FUN (Full-chain and UNcertainty Approaches for Assessing Health Risks in FUture ENvironmental Scenarios www.2-fun.org). 

Another method of predicting human pharmacokinetics is physiologically based pharmacokinetics (PB-PK). The normal pharmacokinetic approach is to try to fit the plasma concentration-time curve to a mathematical function with one, two or three compartments, which are really mathematical constructs necessary for curve fitting, and do not necessarily have any physiological correlates. In PB-PK, the model consists of a series of compartments that are taken to actually represent different tissues [75-77] (Fig. 6.3). In order to build the model it is necessary to know the size and perfusion rate of each tissue, the partition coefficient of the compound between each tissue and blood, and the rate of clearance of the compound in each tissue. Although different sources of errors in the models have been... 

Jones, H.M., Parrott, N., Ohlenbusch, G. and Lave, T. (2006) Predicting pharmacokinetic food effects using biorelevant solubility media and physiologically based modelling. Clinical Pharmacokinetics, 45, 1213—1226. 

Figure 5.5 Flowchart showing various human risk assessment options for chemical mixtures based on component data. PBPK model = Physiologically Based Pharmacokinetic model. 

PBPK model Physiologically based pharmacokinetic model. Physiologically based compartmental model used to characterize pharmacokinetic behavior of a chemical. Available data on blood flow rates, and metabolic and other processes, which the chemical undergoes within each compartment are used to construct a mass-balance framework for the PBPK model. 

Parrott N, Paquereau N, Coassolo P, and Lave T. An Evaluation of the Utility of Physiologically Based Models of Pharmacokinetics in Early Discovery. JPharm... 

Physiologic model-physiologically based pharmacokinetic model (PB/PK) A physiologically based model for Gl transit and absorption in humans is presented. The model can be used to study the dependency of the fraction dose absorbed (Fabs) of both neutral and ionizable compounds on the two main physico-chemical input parameters [the intestinal permeability coefficient (Pint) and the solubility in the intestinal fluids (Sint)] as well as the physiological parameters, such as the gastric emptying time and the intestinal transit time. For permeability-limited compounds, the model produces the established sigmoidal dependence between Fabs and Pnt. In case of solubility-limited absorption, the model enables calculation of the critical mass-solubility ratio, which defines the onset of nonlinearity in the response of fraction absorbed to dose. In addition, an analytical equation to calculate the intestinal permeability coefficient based on the compound s membrane affinity and MW was used successfully in combination with the PB-PK model to predict the human fraction dose absorbed of compounds with permeability-limited absorption. Cross-validation demonstrated a root-mean-square prediction error of 7% for passively absorbed compounds. 

Angelo, M. J., and Pritchard, A. B. (1984). Simulations of methylene chloride pharmacokinetics using a physiologically based model. Regul Toxicol Pharmacol 4, 329-339. 

Hall C, Lueshen E, Mo at A, Linninger AA. 2012. Interspecies scaling in pharmacokinetics a novel whole-body physiologically based modeling framework to discover drug biodistribution mechanisms in vivo. J Pharm Sci 101 1221-1241. 

Absorption, distribution, biotransformation, and excretion of chemical compounds have been discussed as separate phenomena. In reality all these processes occur simultaneously, and are integrated processes, i.e., they all affect each other. In order to understand the movements of chemicals in the body, and for the delineation of the duration of action of a chemical m the organism, it is important to be able to quantify these toxicokinetic phases. For this purpose various models are used, of which the most widely utilized are the one-compartment, two-compartment, and various physiologically based pharmacokinetic models. These models resemble models used in ventilation engineering to characterize air exchange. 

Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models... 

Note This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. 

Krishnan K, Andersen ME, Clewell H 3rd, et al. 1994. Physiologically based pharmacokinetic modeling of chemical mixtures. In Yang R, ed. Toxicology of chemical mixtures. New York, NY Academic Press, 399-437. 

Leung H-W. 1993. Physiologically-based pharmacokinetic modelling. In Ballentine B, Marro T, Turner P, eds. General and applied toxicology. New York, NY Stockton Press, 153-164. 

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. 

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