Abstract
An extended physiological model of methadone disposition in the rat was constructed and evaluated in various tests of model validity. A separate circulation model of the fetus was included due to the large tissue concentration differences obtained after a constant rate infusion but also to propose the use of this type of model for optimization of toxicological tests. Simulations were performed with the animal model and scaled-up models of humans to elucidate the determinants of methadone dispostion. The rationale of the use of an extended model for methadone was also discussed.
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References
T. Teorell. Kinetics of distribution of substances administered to the body: I. The extravascular modes of administration.Arch. Int. Pharmacodyn. Ther. 57:205–225 (1937).
E. J. O'Flaherty.Toxicants and Drugs: Kinetics and Dynamics, Wiley Interscience, New York, 1981.
R. Bellman, J. A. Jacquez, and R. Kalabra. Some mathematical aspects of chemotherapy: I. Organ models.Bull. Math. Biophys. 22:181–198 (1960).
K. B. Bischoff and B. Brown. Drug distribution in mammals.Chem. Eng. Prog. Symp. Ser. 62:33–45 (1966).
D. S. Riggs.The Mathematical Approach to Physiological Problems, Williams and Wilkins, Baltimore, 1963.
K. B. Bischoff and D. L. Dedrick. Thiopental pharmacokinetics.J Pharm. Sci. 57:1346–1351 (1968).
L. E. Gerlowski and R. K. Jain. Physiologically based pharmacokinetic modeling: Principles and applications.J. Pharm. Sci. 72:1103–1127 (1983).
K. B. Bischoff, R. L. Dedrick, and D. S. Zaharko. Preliminary model for methotrexate kinetics.J. Pharm. Sci. 59:149–154 (1970).
K. B. Bischoff. Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.Cancer Chemother. Rep. Part I 59:777–793 (1975).
L. Jansky and H. S. Hart. Cardiac output and organ blood flow in warm- and cold-acclimated rats exposed to cold.Can. J. Physiol. Pharmacol. 46:653–659 (1968).
J. L. Gabrielsson, P. Johansson, U. Bondesson, and L. K. Paalzow. Analysis of methadone disposition in the pregnant rat by means of a physiological flow model.J. Pharmacokin. Biopharm. 13:355–372 (1985).
S. J. Liu, K. Z. C. Chen, and R. I. H. Wang. Effects of desipramine, fecal and urinary excretion of methadone in the rat.J. Pharmacol. Exp. Ther. 198:308–317 (1976).
J. V. Wait and F. Clarke III.DARE-P, A Portable Digital Simulation System, University of Arizona, 1974.
E. R. Carson, C. Cobelli, and L. Finkelstein.The Mathematical Modeling of Metabolic and Endocrine Systems, Wiley, New York, 1983, p. 218.
R. L. Dedrick. Inter-species scaling of regional drug delivery.J. Pharm. Sci. 75:1047–1052 (1986).
E. D. Adolph. Quantitative relations in the physiological constitutions of mamals.Science 109:579–585 (1949).
S. L. Lindstedt and W. A. Calder III. Body size, physiological time and longevity of homeothermic animals.Quart. Rev. Biol. 56:1–16 (1981).
E. F. Yates and P. N. Kugler. Similarity principles and intrinsic geometries—Contrasting approaches to interspecies scaling.J. Pharm. Sci. 75:1019–1027 (1986).
D. E. Hutchings, H. F. Hunt, J. P. Towney, T. S. Rosen, and H. S. Gorinson. Methadone during pregnancy in the rat: Dose level effects on maternal and perinatal mortality and growth in the offspring.J. Pharmacol. Exp. Ther. 197:171–179 (1975).
W. Banner. General principles of clinical pharmacology of the fetus. In H. P. Kuemmerle and K. Brendel (eds.),Clinical Pharmacology in Pregnancy, Thieme-Stratton, New York, 1984, p.132.
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This work was supported by the Svenssons Foundation for Medical Research, the Royal Hvitfeld Establishment, and C. D. Carlssons Foundation.
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Gabrielsson, J.L., Groth, T. An extended physiological pharmacokinetic model of methadone disposition in the rat: Validation and sensitivity analysis. Journal of Pharmacokinetics and Biopharmaceutics 16, 183–201 (1988). https://doi.org/10.1007/BF01062260
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DOI: https://doi.org/10.1007/BF01062260