Pharmacokinetic modelling

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. 

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. 

Andersen ME, MacNaughton MG, Clewell HJ, et al. 1987. Adjusting exposure limits for long and short exposure periods using a physiological pharmacokinetic model. Am Ind Hyg Assoc J 48(4) 335-343. 

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. 

Berellini G, Cruciani G, Mannhold R. Pharmacophore, drug metabolism, and pharmacokinetics models on non-peptide ATi, AT2, and AT1/AT2 angiotensin II receptor antagonists. J Med Chem 2005 48 4389-99. 

Rowland M. Physiologic pharmacokinetic models relevance, experience, and future trends. Drug Metab Rev 1984 15 55-74. 

Nestorov I. Whole body pharmacokinetic models. Clin Pharmacokinet 2003 42 883-908. 

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. 

Useful discussions reviewing PK model structure [12] and PK correlations [13] and describing applications or PK models [14,15] are recommended. Comprehensive reviews of pharmacokinetic modeling are given by Lin and Lu [16] and Sheiner and Steimer [17]. 

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. 

Lntz RJ, Dedrick RL, Matthews FEB, Fling TE, Anderson MW. A preliminary pharmacokinetic model for several chlorinated biphenyls in the rat. Drug Metab Dispos 1977 5 386-396... 

D Sousa RW, Boxenbaum H. Physiological pharmacokinetic models some aspects of theory, practice, and potential. Toxicol Ind Health 1988 4 151-91. 

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. 

Allen BC, Fisher JW. 1993. Pharmacokinetic modeling of trichloroethylene and trichloroacetic acid in humans. Risk Anal 13 71-86. 

Barton HA, Creech JR, Godin CS, et al. 1995. Chloroethylene mixtures Pharmacokinetic modeling and/n vitro metabolism of vinyl chloride, trichloroethylene, and tranv-l,2-dichloroethylene in rats. Toxicol Appl Pharmacol 130 237-247. 

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. 

Dallas CE, Gallo JG, Ramanathan R, et al. 1991. Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats. Toxicol Appl Pharmacol 110 303-314. 

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 ... 

Sato A, Nakajima T, Fujiwara Y, et al. 1977. A pharmacokinetic model to study the excretion of trichloroethylene and its metabolites after an inhalation exposure. Br J Ind Med 34 55-63. 

When we apply these two properties of the Laplace transform to differential equations of our pharmacokinetic model in eq. (39.46), we obtain ... 

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