Pharmacokinetic models physiologically based

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. 

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. 

KrishnanK, Andersen ME. 1994. Physiologically-based pharmacokinetic modeling in toxicology. In Wallace Hayes, ed. Principles and methods of toxicology. 3rd edition. New York, NY Raven Press, Ltd. 

Simulation methods have also been developed that include physiologically based pharmacokinetic modeling (PBPK) and methods such as Cloe PK, OMPPPlus, GastroPlus , SimCYP , and others [122] that are described elsewhere in this book. It is likely that the computational metabolism predictions could be integrated with these to assist in deriving more accurate predictions of human pharmacokinetic parameters. 

Nestorov lA, Aarons LJ, Rowland M. Physiologically based pharmacokinetic modeling of a homologous series of barbiturates in the rat a sensitivity analysis. / Pharmacokinet Biopharm 1997 25 413-47. 

Figure 22.1 A. Schema for a physiologically based pharmacokinetic model incorporating absorption in the stomach and intestines and distribntion to various tissues. B. Each organ or tissue type includes representation of perfusion (Q) and drug concentrations entering and leaving the tissue. Fluxes are computed by the product of an appropriate rate law, and permeable surface area accounts for the affinity (e.g., lipophilic drugs absorbing more readily into adipose tissue). Clearance is computed for each tissue based on physiology and is often assumed to be zero for tissues other than the gut, the liver, and the kidneys.

Nestorov lA, Aarons LJ, Arundel PA, Rowland M. Lumping of whole-body physiologically based pharmacokinetic models. JPharmacokinet Biopharm 1998 Feb 26(l) 21-46. 

Clewell HJ 3rd, Gentry PR, Covington TR, Gearhart JM. Development of a physiologically based pharmacokinetic model of trichloroethylene and its metabolites for use in risk assessment. Environ Health Perspect 2000 May 108 Suppl 2 283-305. 

Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. J Pharm Sci 2002 May 91(5) 1358-70. 

Bjorkman S, Wada DR, Berling BM, Benoni G. Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model. J Pharm Sci 2001 Sep 90(9) 1226-41. 

Charnick SB, Kawai R, Nedelman JR, Lemaire M, Niederberger W, Sato H. Perspectives in pharmacokinetics. Physiologically based pharmacokinetic modeling as atoolfor drug development./P/jarmacokmefTEop/jarm 1995 Apr 23(2) 217-29. Review. 

Theil FP, Guentert TW, Haddad S, Poulin P. Utility of physiologically based pharmacokinetic models to drug development and rational drug discovery candidate selection. Toxicol Lett 2003 Feb 18 138(l-2) 29-49. Review. 

Reddy M, Yang RSH, Clewell HJ, Andersen ME (eds). Physiologically based pharmacokinetic modeling. Zurich Wiley VCH, 2005. 

Chen HS, Gross JF. Physiologically based pharmacokinetic models for anticancer drngs. Cancer Chemother Pharmacol 1979 2(2) 85-94. Review. 

The Chemical Manager and Authors acknowledge the contribution of Dr. Ted W. Simon, U.S. EPA, in applying physiologically-based pharmacokinetic modeling to the development of minimal risk levels for trichloroethylene. 

Cronin WJ, Oswald EJ, Shelley ML, et al. 1995. A trichloroethylene risk assessment using a Monte Carlo analysis of parameter uncertainty in conjunction with physiologically-based pharmacokinetic modeling. Risk Anal 15 555-565. 

Fisher JW, Whittaker TA, Taylor DH, et al. 1989. Physiologically based pharmacokinetic modeling of the pregnant rat A multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid. Toxicol Appl Pharmacol 99 395-414. 

Krishnan K, Andersen ME. 1994. Physiologically based pharmacokinetic modeling in toxicology. In ... 

Figure 2 Individual organ representations for a three-subcompartment (A), two-subcompartment (B), or typical membrane-linked and blood flow-limited (C) physiologically based pharmacokinetic model. See text for definition of symbols.

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. 

Figure 3 Possible blood circulation connections in a physiologically based pharmacokinetic model. (A) Venous return incorporated into lung mass balance equation (B) separate venous blood compartment. See text for definition of symbols.

Y Igari, Y Sugiyama, Y Sawada, T Iga, M Hanano. Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model. J Pharmacokin Biopharm 11 577-593, 1983. 

LE Gerlowski, RK Jain. Physiologically based pharmacokinetic modeling Principles and applications. J Pharm Sci 72 1103-1127, 1983. 

RP Brown, MD Delp, SL Lindstedt, LR Rhomberg, RP Beliles. Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13 407-484, 1997. 

FY Bois, TJ Woodruff, RC Spear. Comparison of three physiologically based pharmacokinetic models of benzene disposition. Toxicol Appl Pharmacol 110 79-88, 1991. 

RS Thomas, WE Lytle, TJ Keefe, AA Constan, RSH Yang. Incorporating Monte Carlo simulation into physiologically based pharmacokinetic models using advanced continuous simulation language (ACSL) A computational method. Fundam Appl Toxicol 31 19-28, 1996. 

Absorbed lead is distributed in various tissue compartments. Several models of lead pharmacokinetics have been proposed to characterize such parameters as intercompartmental lead exchange rates, retention of lead in various pools, and relative rates of distribution among the tissue groups. See Section 2.3.5 for a discussion of the classical compartmental models and physiologically based pharmacokinetic models (PBPK) developed for lead risk assessments. 

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