Abstract
Compartmental models are composed of sets of interconnected mixing chambers or stirred tanks. Each component of the system is considered to be homogeneous, instantly mixed, with uniform concentration. The state variables are concentrations or molar amounts of chemical species. Chemical reactions, transmembrane transport, and binding processes, determined in reality by electrochemical driving forces and constrained by thermodynamic laws, are generally treated using first-order rate equations. This fundamental simplicity makes them easy to compute since ordinary differential equations (ODEs) are readily solved numerically and often analytically. While compartmental systems have a reputation for being merely descriptive they can be developed to levels providing realistic mechanistic features through refining the kinetics. Generally, one is considering multi-compartmental systems for realistic modeling. Compartments can be used as “black” box operators without explicit internal structure, but in pharmacokinetics compartments are considered as homogeneous pools of particular solutes, with inputs and outputs defined as flows or solute fluxes, and transformations expressed as rate equations.
Descriptive models providing no explanation of mechanism are nevertheless useful in modeling of many systems. In pharmacokinetics (PK), compartmental models are in widespread use for describing the concentration–time curves of a drug concentration following administration. This gives a description of how long it remains available in the body, and is a guide to defining dosage regimens, method of delivery, and expectations for its effects. Pharmacodynamics (PD) requires more depth since it focuses on the physiological response to the drug or toxin, and therefore stimulates a demand to understand how the drug works on the biological system; having to understand drug response mechanisms then folds back on the delivery mechanism (the PK part) since PK and PD are going on simultaneously (PKPD).
Many systems have been developed over the years to aid in modeling PKPD systems. Almost all have solved only ODEs, while allowing considerable conceptual complexity in the descriptions of chemical transformations, methods of solving the equations, displaying results, and analyzing systems behavior. Systems for compartmental analysis include Simulation and Applied Mathematics, CoPasi (enzymatic reactions), Berkeley Madonna (physiological systems), XPPaut (dynamical system behavioral analysis), and a good many others. JSim, a system allowing the use of both ODEs and partial differential equations (that describe spatial distributions), is used here. It is an open source system, meaning that it is available for free and can be modified by users. It offers a set of features unique in breadth of capability that make model verification surer and easier, and produces models that can be shared on all standard computer platforms.
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References
Berman M (1963) The formulation and testing of models. Ann N Y Acad Sci 108:182–194
Jacquez JA (1972) Compartmental analysis in biology and medicine. Kinetics of distribution of tracer-labeled materials. Elsevier Publishing Co, Amsterdam, 237 pp
Jacquez JA (1996) Compartmental analysis in biology and medicine, 3rd edn. BioMedware, Ann Arbor, MI, 514 pp
Cobelli C, Foster D, Toffolo G (2000) Tracer kinetics in biomedical research. From data to model. Kluwer Academic, New York
Zierler KL (1981) A critique of compartmental analysis. Annu Rev Biophys Bioeng 10:531–562
Anderson JC, Bassingthwaighte JB (2007) Tracers in physiological systems modeling. Chapter 8 Mathematical modeling in nutrition and agriculture. In: Mark D. Hanigan JN, Casey L Marsteller. Proceedings of the ninth international conference on mathematical modeling in nutrition, Roanoke, VA, 14–17 August 2006, Virginia Polytechnic Institute and State University Blacksburg, VA, pp 125–159
Knopp TJ, Anderson DU, Bassingthwaighte JB (1970) SIMCON–Simulation control to optimize man-machine interaction. Simulation 14:81–86
Sauro HM, Fell DA (1991) SCAMP: a metabolic simulator and control analysis program. Math Comput Model 15:15–28
Sauro HM, Hucka M, Finney A, Bolouri H (2001) The systems biology workbench concept demonstrator: design and implementation. Available via the World Wide Web at http://www.cds.caltech.edu/erato/sbw/docs/detailed-design/
Raymond GM, Butterworth E, Bassingthwaighte JB (2003) JSIM: free software package for teaching physiological modeling and research. Exp Biol 280.5:102. (www.physiome.org/jsim)
Chizeck HJ, Butterworth E, Bassingthwaighte JB (2009) Error detection and unit conversion. Automated unit balancing in modeling interface systems. IEEE Eng Med Biol 28(3):50–58
Platt JR (1964) Strong inference. Science 146:347–353
Bassingthwaighte JB, Chinard FP, Crone C, Goresky CA, Lassen NA, Reneman RS, Zierler KL (1986) Terminology for mass transport and exchange. Am J Physiol Heart Circ Physiol 250:H539–H545
Benedek IH, Joshi AS, Pieniazek JH, King S-YP, Kornhauser DM (1995) Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. J Clin Pharmacol 35:1181–1186
Aarons L, Hopkins K, Rowland M, Brossel S, Thiercelin JF (1989) Route of administration and sex differences in the pharmacokinetics of aspirin, administered as its lysine salt. Pharm Res 6:660–666
Prescott LF, Balali-Mood M, Critchley JAJH, Johnstone AF, Proudfoot AT (1982) Diuresis or urinary alkalinisation for salicylate poisoning? Br Med J 285:1383–1386
Chan IS, Goldstein AA, Bassingthwaighte JB (1993) SENSOP: a derivative-free solver for non-linear least squares with sensitivity scaling. Ann Biomed Eng 21:621–631
Glad T, Goldstein A (1977) Optimization of functions whose values are subject to small errors. BIT 17:160–169
Dennis JE, Schnabel RB (1983) Numerical methods for unconstrained optimization and nonlinear equation. Prentice-Hall, New York
Fox IJ, Brooker LGS, Heseltine DW, Essex HE, Wood EH (1957) A tricarbocyanine dye for continuous recording of dilution curves in whole blood independent of variations in blood oxygen saturation. Proc Staff Meet Mayo Clin 32:478
Edwards AWT, Isaacson J, Sutterer WF, Bassingthwaighte JB, Wood EH (1963) Indocyanine green densitometry in flowing blood compensated for background dye. J Appl Physiol 18:1294–1304
Edwards AWT, Bassingthwaighte JB, Sutterer WF, Wood EH (1960) Blood level of indocyanine green in the dog during multiple dye curves and its effect on instrumental calibration. Proc Staff Meet Mayo Clin 35:747–751
Bassingthwaighte JB (1966) Plasma indicator dispersion in arteries of the human leg. Circ Res 19:332–346
Hunton DB, Bollman JL, Hoffman HN (1961) The plasma removal of indocyanine green and sulfobromophthalein: effect of dosage and blocking agents. J Clin Invest 30(9):1648–1655 (PMCID PMC290858)
Bassingthwaighte JB, Edwards AWT, Wood EH (1962) Areas of dye-dilution curves sampled simultaneously from central and peripheral sites. J Appl Physiol 17:91–98
Stewart GN (1897) Researches on the circulation time and on the influences which affect it: IV. The output of the heart. J Physiol 22:159–183
Hamilton WF, Moore JW, Kinsman JM, Spurling RG (1932) Studies on the circulation. IV. Further analysis of the injection method, and of changes in hemodynamics under physiological and pathological conditions. Am J Physiol 99:534–551
Thompson HK, Starmer CF, Whalen RE, McIntosh HD (1964) Indicator transit time considered as a gamma variate. Circ Res 14:502–515
Bassingthwaighte JB, Ackerman FH, Wood EH (1966) Applications of the lagged normal density curve as a model for arterial dilution curves. Circ Res 18:398–415
Krenn CG, Krafft P, Schaefer B, Pokorny H, Schneider B, Pinsky MR, Steltzer H (2000) Effects of positive end-expiratory pressure on hemodynamics and indocyanine green kinetics in patients after orthotopic liver transplantation. Crit Care Med 28:1760–1765
Krenn CG, Pokorny H, Hoerauf K, Stark J, Roth E, Steltzer H, Druml W (2008) Non-isotopic tyrosine kinetics using an alanyl-tyrosine dipeptide to assess graft function in liver transplant recipients - a pilot study. Wien Klin Wochenschr 120(1–2):19–24
Kortgen A, Paxian M, Werth M, Recknagel P, Rauschfusz F, Lupp A, Krenn C, Muller D, Claus RA, Reinhart K, Settmacher U, Bauer M (2009) Prospective assessment of hepatic function and mechanisms of dysfunction in the critically ill. Shock 32(4):358–365
Bassingthwaighte JB, Yipintsoi T, Harvey RB (1974) Microvasculature of the dog left ventricular myocardium. Microvasc Res 7:229–249
Chinard FP, Vosburgh GJ, Enns T (1955) Transcapillary exchange of water and of other substances in certain organs of the dog. Am J Physiol 183:221–234
Crone C (1963) The permeability of capillaries in various organs as determined by the use of the indicator diffusion method. Acta Physiol Scand 58:292–305
Kuikka J, Levin M, Bassingthwaighte JB (1986) Multiple tracer dilution estimates of d- and 2-deoxy-d-glucose uptake by the heart. Am J Physiol Heart Circ Physiol 250:H29–H42
Krogh A (1919) The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue. J Physiol (Lond) 52:409–415
Sangren WC, Sheppard CW (1953) A mathematical derivation of the exchange of a labeled substance between a liquid flowing in a vessel and an external compartment. Bull Math Biophys 15:387–394
Renkin EM (1959) Transport of potassium-42 from blood to tissue in isolated mammalian skeletal muscles. Am J Physiol 197:1205–1210
Bassingthwaighte JB (1974) A concurrent flow model for extraction during transcapillary passage. Circ Res 35:483–503
Bassingthwaighte JB, Wang CY, Chan IS (1989) Blood-tissue exchange via transport and transformation by endothelial cells. Circ Res 65:997–1020
Bassingthwaighte JB, Chan IS, Wang CY (1992) Computationally efficient algorithms for capillary convection-permeation-diffusion models for blood-tissue exchange. Ann Biomed Eng 20:687–725
TOMS./TOMS. Association of computing machinery: transactions on mathematical software. http://www.netlib.org/toms/index.html
Yipintsoi T, Scanlon PD, Bassingthwaighte JB (1972) Density and water content of dog ventricular myocardium. Proc Soc Exp Biol Med 141:1032–1035
Vinnakota K, Bassingthwaighte JB (2004) Myocardial density and composition: a basis for calculating intracellular metabolite concentrations. Am J Physiol Heart Circ Physiol 286:H1742–H1749
Bassingthwaighte JB, Raymond GR, Ploger JD, Schwartz LM, Bukowski TR (2006) GENTEX, a general multiscale model for in vivo tissue exchanges and intraorgan metabolism. Phil Trans Roy Soc A Math Phys Eng Sci 364(1843):1423–1442. doi: 10.1098/rsta.2006.1779
Bassingthwaighte JB, Goresky CA, Linehan JH (1998) Ch. 1 Modeling in the analysis of the processes of uptake and metabolism in the whole organ. In: Bassingthwaighte JB, Goresky CA, Linehan JH (eds) Whole organ approaches to cellular metabolism. Springer, New York, pp 3–27
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Bassingthwaighte, J.B., Butterworth, E., Jardine, B., Raymond, G.M. (2012). Compartmental Modeling in the Analysis of Biological Systems. In: Reisfeld, B., Mayeno, A. (eds) Computational Toxicology. Methods in Molecular Biology, vol 929. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-050-2_17
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