Abstract
A flow-limited physiologic mathematical model has been developed to describe the time course of 2′deoxycoformycin (2′dCF) concentrations in the plasma and tissues of mice following iv and ip doses. Urinary excretion is modeled as a linear process involving filtration and secretion, since kidney clearance exceeded estimated glomerular filtration rate. Intracellular binding is described as the sum of linear nonspecific binding plus strong saturable binding to adenosine deaminase. Pharmacokinetic parameters are determined by a sequential optimization scheme in which each tissue is studied by means of a hybrid model. The model has been used to predict pharmacokinetic behaviour of 2′dCF in both normal and leukemic mice, and model simulations are compared with published data.
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P. W. K. Woo, H. W. Dion, S. M. Lange, L. F. Dahl, and L. J. Durham. A novel adenosine and ara-A deaminase inhibitor, (R)-3-(2-deoxy-beta-D-erythropen- tofuranosyl)-3,6,7,8-tetrahydroimidazo(4,5-d)(1,3) diazepin-8-ol.J. Heterocyclic. Chem. 11:641–643 (1974).
R. P. Agarwal, T. Spector, and R. E. Parks, Jr. Tight binding inhibitors-IV. Inhibition of adenosine deaminases by various inhibitors.Biochem. Pharmacol. 26:359–367 (1977).
G. A. LePage, L. S. Worth, and A. P. Kimball. Enhancement of the antitumor activity of arabinofuranosyladenine by 2′-deoxycoformycin.Cancer Res. 36:1481–1485 (1976).
T. G. Brady and C. I. O'Donovan. A study of the tissue distribution of adenosine deaminase in six mammal species.Comp. Biochem. Physiol. 14:101–120 (1965).
S. H. Lee, N. Caron, and A. P. Kimball. Therapeutic effects of 9-B-D-arabinofuranosyladenine and 2′-deoxycoforrnycin combinations on intracerebral leukemia.Cancer Res. 37:1953–1955 (1977).
R. H. Adamson, D. W. Zaharevitz, and D. G. Johns. Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2′-deoxycoformycin.Pharmacology 15:84–89 (1977).
R. H. Adamson, M. M. Chassin, M. A. Chirigos, and D. G. Johns. Some aspects of the pharmacology of the adenosine deaminase inhibitors 2′deoxycoformycin and erythro-9-(2-hydroxy-3-nonyl)-adenine. InCurrent Chemotherapy II, W. Siezenthalis and R. Luthy (eds.). American Society for Microbiology, Washington, D.C., 1978, pp. 1116–1118.
J. F. Smith, R. C. Young, and D. M. Young. In vivo toxicity to lymphoid tissue by 2′deoxycoformycin.Cancer Chemother. Pharmacol. 1:49–51 (1978).
W. R. McConnell, R. L. Furner, and D. L. Hill. Pharmacokinetics of 2′deoxycoformycin in normal and L1210 leukemic mice.Drug Metab. Dispos. 7:11–13 (1979).
W. R. McConnell, W. J. Suling, L. S. Rice, W. M. Shannon, and D. L. Hill. The use of microbiological and enzymatic assays in studies of the disposition of 2′-deoxycoformycin in the mouse.Cancer Treat. Rep. 62:1153–1159 (1978).
M. M. Chassin, R. H. Adamson, D. W. Zaharevitz, and D. G. Johns. Enzyme inhibition titration assay for 2′deoxycoformycin and its applications to the study of the relationship between drug concentration and tissue adenosine deaminase in dogs and rats,Biochem. Pharmacol. 28:1849–1855 (1979).
K. J. Himmelstein and R. J. Lutz. A review of the applications of physiologically based pharmacokinetic modeling.J. Pharmacokinet. Biopharm. 7:127–145 (1979).
K. B. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. A. Longstreth. Methotrexate pharmacokinetics.J. Pharm. Sci. 60:1128–1133 (1971).
P. E. Barondy, T. Chang, E. Maschewske, and A. J. Glazko. Inhibition of adenosine deaminase by co-vidarabine and its effects on the metabolic disposition of adenine arabinoside (Vidarabine).Ann. N.Y. Acad. Sci. 284:9–20 (1977).
F. G. King and R. L. Dedrick. Pharmacokinetic model for 2-aminothiadiazole in mouse, dog and monkey.Cancer Treat. Rep. 63:1939–1947 (1979).
J. F. Smyth, R. M. Paine, A. L. Jackman, K. R. Harrap, M. M. Chassin, R. H. Adamson, and D. G. Johns. The clinical pharmacology of adenosine deaminase inhibitor 2′-deoxycoformycin.Cancer Chemother. Pharmacol. 5:93–101 (1980).
P. M. Venner and R. I. Glazer. The metabolism of 2′deoxycoformycin by L1210 cells in vitro.Biochem. Pharmacol. 28:3239–3242 (1979).
R. L. Dedrick, D. D. Forrester, J. N. Cannon, S. M. El Dareer, and L. B. Mellett. Pharmacokinetics of 1-beta-d-arabinofuranosylcytosine (Ara-C) deamination in several species.Biochem. Pharmacol. 22:2405–2417 (1973).
J. E. Fletcher and R. I. Shrager.Users Guide to Least Squares Model Fitting. Technical Report No. 1, Division of Computer Research and Technology, National Institute of Health, Washington D.C. 1968.
R. J. Lutz, R. L. Dedrick, J. A. Straw, M. M. Hart, P. Klubes, and D. S. Zaharko. The kinetics of methotrexate distribution in spontaneous canine lymphosarcoma.J. Pharmacokin. Biopharm. 3:77–97 (1975).
J. M. Weissbrod and R. K. Jain. Preliminary model for streptozocin metabolism in mice.J. Pharm. Sci. 69:691–694 (1980).
R. J. Lutz, R. L. Dedrick, and D. S. Zaharko. Physiological pharmacokinetics: anin vivo approach to membrane transport.Pharmacol. Ther. 11:559–592 (1980).
A. Tedde, M. E. Balis, R. Schonberg, and P. P. Trotta. Effects of 2′deoxycoformycin infusion on mouse adenosine deaminase.Cancer Res. 39:3044–3050 (1979).
J. A. Straw, M. M. Hart, P. Klubes, D. S. Zaharko, and R. L. Dedrick. Distribution of anticancer agents in spontaneous animal tumors. I. Regional blood flow and methotrexate distribution in canine lymphosarcoma.J.N.C.I. 52:1327–1331 (1974).
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King, F.G., Dedrick, R.L. Physiologic model for the pharmacokinetics of 2′deoxycoformycin in normal and leukemic mice. Journal of Pharmacokinetics and Biopharmaceutics 9, 519–534 (1981). https://doi.org/10.1007/BF01061024
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DOI: https://doi.org/10.1007/BF01061024