Abstract
The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethylnitrosamine (DMNA). The pharmacokinetics of theophylline were studied after a single intravenous or a single oral administration. Using the ultrafiltration method, protein-drug binding experiments were also carried out. The bilirubin level was several-fold increased by BDL, but not by DMNA treatment. The albumin content was decreased in both cirrhotic groups. The total clearance (Clt, ml/kg/hr) of theophylline in both hepatic cirrhosis groups significantly decreased and the terminal half-life (t1/2) in the cirrhotic rats was increased about two-fold after intravenous and oral administration. The volume of distribution at steady state (Vdss, ml/kg) was increased slightly in the cirrhotic groups. Protein binding in BDL (8.67±4.85%) decreased about four-folds, but in DMNA (73.00±9.85%) similar result, was observed as compared with the control. Increased free fraction of theophylline did not increase the volume of distribution in BDL. Therefore decreased total body clearance of theophylline was mainly due to decreased intrinsic clearance of theophylline in the liver. The absolute bioavailability of theophylline in these experiments was between 63.8 and 72.8%(66.1% in BDL, 63.8% in Sham operated and Control, 72.8% in DMNA). These results suggest that in the experimental hepatic cirrhosis model, administration route does not affect the disposition of theophylline.
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References
Ala-Kokko, L., Stenback, F. and Ryhanen, L., Preventive effect of malotilate on dimethylnitrosamine-induced liver fibrosis in the rat.J. Lab. Clin. Med. 113, 177–183 (1989).
Bickel, M., Baader, E., Brocks, D. G., Engelbart, K., Günzler, V., Schmidts, E. and Vogel, G. H., Beneficial effects of inhibitors of prolyl 4-hydroxylase in CCl4-induced fibrosis of the liver in rats.J. Hepatol. 13(suppl. 3), S26-S34 (1991).
Boker, K., Schwarting, G., Kaule, G., Gunzler, V., and Schmidt, E., Fibrosis of the liver in rats induced by bile duct ligation: Effect of inhibition of prolyl 4-hydroxylase.J. Hepatol. 13(suppl. 3), S35-S40 (1991).
National Statistical Office, Korea,Annual report on the cause of death statistics. (1991, 1992, 1993, 1994).
Gomita, Y., Furuno, K., Eto, K., Okazaki, M., Suemaru, K., and Araki, Y., Effect of cigarette smoking on theophylline pharmacokinetics in rats.J. Pharm. Pharmacol., 43, 621–624 (1991).
Han, S. S., Kim, K. Y., Ham, S. H., Sohn, D. H., and Kim, J. B., Pharmacokinetics of theophylline: Effects of hepatic fibrosis in rats induced by bile duct ligation.Biol. Pharm. Bull., 18, 470–473 (1995).
Hendeles, L., Weinberger, M., and Bighley, L., Absolute bioavailability of oral theophylline.Am. J. Hosp. Pharm. 34, 525–527 (1977).
Jamall, I. S., Finelli, V. N. and Que Hee, S. S., A simple method, to determine nanogram levels of 4-hydroxyproline in biological tissues.Anal. Biochem. 112, 70–75 (1981).
Jezequel, A. M., Mancini, R., Rinaldesi, M. L., Macarri, G., Venturini, C. and Orlandi, F., A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat.J. Hepatol. 5, 174–181 (1987).
Kountouras, J., Billing, B. H. and Scheuer, P. J., Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat.Br. J. Exp. Path. 65, 305–311 (1984).
Lesko, L. J., Tabor, K. J. and Johnson, B. F., Theophylline serum protein binding in obstructive airways disease.Clin. Pharmacol. Ther. 29, 776–781 (1981).
Mangione, A., Imhoff, T. E., Lee, R. V., Shum, L. Y., and Jusko, W. J., Pharmacokinetics of theophylline in hepatic disease.Chest 73, 616–622 (1978).
Orcutt, J. J., Kozak, P. P., Gillman, S. A. and Cummins, L. H., Microscale method for theophylline in body fluids by reversed-phase high pressure liquid chromatography.Clin. Chem. 23, 599–601 (1977).
Piafsky, K. M., Sitar, D. S., Rangno, R. E. and Ogilvie, R. I., Theophylline disposition in patients with hepatic cirrhosis.N. Engl. J. Med. 296, 1495–1497 (1977).
Shand, D. G., Drug disposition in liver disease.N. Engl. J. Med. 296, 1527–1528 (1977).
Shargel, L. and Yu, A.B.C.,Applied Biopharmaceutics and Pharmacokinetics. 3rd Ed., Prentice-Hall Intl. Inc., New Jersey, pp. 595, 1993.
Tamayo, R. P., Is cirrhosis, of the liver experimentally produced by CCl4 an adequate model of human cirrhosis?.Hepatology 3, 112–120 (1983).
Tsukamoto, H., Matsuoka, M. and French, S. W., Experimental model of hepatic fibrosis: a review.Sem. Liv. Dis. 10, 56–65 (1990).
Wilkinson, G. R. and Branch, R. A., Effects of hepatic disease on clinical pharmacokinetics. In Benet L. Z., Massoud, N., and Gambertoglio, J. G. (Eds.),Pharmacokinetic Basis for Drug Treatment. Raven Press, New York, pp. 49–61, 1984.
Williams, R. L., Drug administration in hepatic disease.N. Engl. J. Med. 309, 1616–1622 (1983).
øie, S. and Tozer, T. N., Effect of altered plasma protein binding on apparent volume of distribution.J. Pharm. Sci. 68, 1203–1205 (1979).
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Nam, B.H., Sohn, D.H., Ko, G. et al. Effect of hepatic cirrhosis on the pharmacokinetics of theophylline in rats. Arch. Pharm. Res. 20, 318–323 (1997). https://doi.org/10.1007/BF02976193
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DOI: https://doi.org/10.1007/BF02976193