Physiologically based models model structure

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. 

Physiologically based pharmacokinetic models provide a format to analyze relationships between model parameters and physicochemical properties for a series of drug analogues. Quantitative structure-pharmacokinetic relationships based on PB-PK model parameters have been pursued [12,13] and may ultimately prove useful in the drug development process. In this venue, such relationships, through predictions of tissue distribution, could expedite drug design and discovery. 

Fig. 17.5 Schematic representation of a physiological based model. Left figure shows the physiological structure, upper right figure shows a model for a perfusion rate limited tissue, and lower right figure shows a model for a permeability rate-limited tissue. Q denotes the blood flow, CL the excretion rate, KP the tissuerplasma distribution coefficient, and PS the permeability surface area coefficient.

Beliveau M, Tardif R, Krishnan K. 2003. Quantitative structure-property relationships for physiologically based pharmacokinetic modeling of volatile organic chemicals in rats. Toxicol Appl Pharmacol 189 221-232. 

Parham FM, Portier CJ. 1998. Using structural information to create physiologically based pharmacokinetic models for all polychlorinated biphenyls. E-Rates of metabolism. Toxicol Appl Pharmacol 151(1) 110-116. 

Nestorov, I. A. (1999). Sensitivity analysis of [4iarmacokinetic and pharmacodynamic systems 1. A structural approach to sensitivity analysis of physiologically based pharmacokinetic models. J Pharmacokinet Biopharm 27, 577-596. 

Poulin P, Krishnan K. 1996b. Molecular structure-based prediction of the partition coefficients of organic chemicals for physiologically-based pharmacokinetic models. Toxicol Method 6 117-137. 

In terms of the visual clarity of its presentation, biochemistry has still to catch up with anatomy and physiology. In this book, we sometimes use simplified ball-and-stick models instead of the classical chemical formulae. In addition, a number of compounds are represented by space-filling models. In these cases, we have tried to be as realistic as possible. The models of small molecules are based on conformations calculated by computer-based molecular modeling. In illustrating macromolecules, we used structural infor-... 

Poulin and Krishnan (1995) developed a method to predict tissue blood PCs for incorporation into physiologically based pharmacokinetic (PBPK) models. Tissue blood partitioning was calculated as an additive function of partitioning into the water, neutral lipids and phospholipids constituent of individual tissues. These were calculated using published values for lipid and water content of tissues and the octanol-water PC of the compounds. Poulin and Krishnan (1998 1999) used this method to predict tissue blood PCs that were subsequently incorporated into a quantitative structure-toxicokinetic model. The prediction of tissue plasma PCs to describe distribution processes and as input parameters for PBPK models has been extensively researched by Poulin and coworkers a great deal of further information can be obtained from their references (Poulin and Theil, 2000 Poulin et al., 2001 Poulin and Theil, 2002a Poulin and Theil, 2002b). 

Many types of modeling techniques are available in the discovery phase of drug development, from structure activity relationships (SAR) to physiology based pharmacokinetics (PBPK) and pharmacokinetics-/pharmacodynamics (PK/PD) to help choosing some of the lead compounds. Some tests that are carried out by discovery include techniques related to structure determination, metabolism, and permeability NMR, MS/MS, elemental analysis, PAMPA, CACO-2, and in vitro metabolic stability. Although they are important as a part of physicochemical molecular characterization under the biopharmaceutics umbrella, they will not be discussed here. The reader can find relevant information in numerous monographs [9,10]. 

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