Abstract
Tissue distribution kinetics of tetraethylammonium (TEA) ion in rats were studied following both constant-rate intravenous infusion and rapid intravenous injection of the drug. At a steady-state plasma concentration of 0.2 μg/ml, the tissue-to-plasma (T/P) concentration ratio of the kidneys, liver, heart, gut, and lungs exceeded 1,indicating that TEA is localized in these tissues. In vitrotissue homogenate binding and slice uptake experiments provided no evidence of TEA binding to tissue constituents, suggesting that the high T/P concentration gradient is due to an active transport process. The maximum concentration of TEA in all tissues occurred within 5–15 min after rapid injection of a 2-mg dose. Except for the liver, the subsequent decline of TEA concentration in various tissues over a 5-hr period was slow compared to that in plasma. Consequently, the T/P ratio of liver and kidney remained relatively constant, while those of the other tissues increased continually with time. These features of TEA tissue distribution kinetics can be predicted by a physiologically based pharmacokinetic model which incorporates both active and passive transport processes for the passage of TEA between blood and the tissue mass.
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References
K. J. Himmelstein and R. J. Lutz. A review of the applications of physiologically based pharmacokinetic modeling.J. Pharmacokin. Biopharm. 7:127–145 (1979).
N. Benowitz, R. P. Forsyth, K. L. Melmon, and M. Rowland. Lidocaine disposition kinetics in monkey and man. II. Effects of hemorrhage and sympathomimetic drug administration.Clin. Pharmacol. Ther. 16:99–109 (1974).
R. L. Dedrick. Animal scale-up.J. Pharmacokin. Biopharm. 1:435–461 (1973).
H. Shindo, I. Takahashi, and E. Nakajima. Autoradiographic studies on the distribution of quaternary ammonium compounds. II. Distribution of14C-labelled decamethonium, hexamethonium and dimethonium in mice.Chem. Pharm. Bull. 19:1876–1885 (1971).
J. R. Weeks and J. D. Davis. Chronic intravenous cannulas for rats.J. Appl. Physiol. 19:540–541 (1964).
L. S. Schanker and A. S. Morrison. Physiological disposition of guanethidine in the rat and its uptake by heart slices.Int. J. Neuropharmacol. 4:27–39, (1965).
J. R. Ronbinson. Some effects of glucose and calcium upon the metabolism of kidney slices from adult and newborn rats.Biochem. J. 45:68–74 (1949).
K. A. Dandekar and H. B. Kostenbauder. Effect of sodium salicylate on renal elimination of a quaternary ammonium compound.J. Pharm. Sci. 66:56–60 (1977).
W. D. Conway, V. K. Batra, and A. Abramowitz. High voltage paper electrophoresis for characterization of drug metabolites.J. Pharm. Sci. 62:1810–1817 (1973).
R. D. Hughes, P. Milburn, and R. T. Williams. Molecular weight as a factor in the excretion of monoquaternary ammonium cations in the bile of the rat, rabbit and guinea pig.Biochem. J. 136:967–978 (1973).
C. M. Metzler.NONLIN: A Computer Program for Parameter Estimation in Nonlinear Situations, Technical Report 7292/69/7293/005, Upjohn Co., Kalamazoo, Mich. November 25, 1969.
M. Gibaldi and D. Perrier. Pharmacokinetics. In J. Swarbrick (ed.),Drugs and the Pharmaceutical Sciences. Dekker, New York, 1975, p. 89.
P. L. Altman and D. S. Dittmer (eds.),Biology Data Book, 2nd ed., Vol. III, Federation of American Scoieties for Experimental Biology, Bethesda, Md., 1974.
B. R. Rennick and G. K. Moe. Stop flow localization of renal tubular excretion of tetraethylammonium.Am. J. Physiol. 198:1267–1270 (1960).
K. Turnheim and F. O. Lauterbach. Absorption and secretion of monoquaternary ammonium compounds by the isolated intestinal mucosa.Biochem. Pharmacol. 26:99–108 (1977).
J. Holm. Transport and exchange of tetraethylammonium in mouse kidney cortical slices.Biochem. Pharmacol. 27:999–1003 (1978).
B. Rennick, B. Hamilton, and R. Evans. Development of renal tubular transports of TEA and PAH in the puppy and piglet.Am. J. Physiol. 201:743–746 (1961).
P. L. Altman and D. S. Dittmer (eds.),Biological Handbooks—Blood and Other Body Fluids, Federation of American Societies for Experimental Biology, Washington, D.C. 1961.
K. B. Bischoff, R. L. Dedrick, D. S. Zaharko, and J. A. Longstreth. Methotrexate pharmacokinetics.,J. Pharm. Sci. 60:1128–1133 (1971).
T. G. Coleman, R. D. Manning, Jr., R. A. Norman, Jr., and A. C. Guyton. Dynamics of water isotope distribution.Am. J. Physiol. 223:1371–1375 (1972).
R. M. Levine, M. R. Blair, and B. B. Clark. Factors influencing the intestinal absorption of certain monoquaternary anticholinergic compounds with special reference to benzomethamine [N-diethylaminoethyl-N′-methyl-benzilamide methobromide (MC-3199)].J. Pharmacol. Exp. Ther. 114:78–86 (1955).
F. B. Hildebrand.Introduction to Numerical Analysis. 2nd ed., McGraw-Hill, New York, 1974, p. 252.
A. Rescigno and G. Segre.Drug and Tracer Kinetics, 1st ed. (American), Blaisdell, Waltham, Massachusetts, 1966, p. 91.
G. Levy and M. Gibaldi. Pharmacokinetics. In O. Eichler, A. Farah, H. Herken, A. D. Welch, (eds.),Handbook of Experimental Pharmacology, Vol. XXVIII/3, Springer-Verlag, New York, 1975, p. 19.
K. A. Pittman and G. A. Portmann, Pharmacokinetics of pentazocine in the rhesus monkey.J. Pharm. Sci. 63:84–88 (1974).
L. L. Miller. Physiological factors and liver cell function.J. Histochem. Cytochem. 7:235–236 (1959).
G. Barber-Riley. Uptake of bromosulphthalein by incubated rat liver slices.S. Afr. J. Med. 26:91–97 (1961).
C. D. Thron. Some remarks on compartment analysis of uptake and washout data.Life Sci. 22:1287–1304 (1978).
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This work was supported in part by United States Public Health Service Grants No. GM-20852 (M. G. and D. D. S.), GM-15956 (D. D. S.), and RR-07037 (K. J. H.).
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Mintun, M., Himmelstein, K.J., Schroder, R.L. et al. Tissue distribution kinetics of tetraethylammonium ion in the rat. Journal of Pharmacokinetics and Biopharmaceutics 8, 373–409 (1980). https://doi.org/10.1007/BF01059385
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DOI: https://doi.org/10.1007/BF01059385