Archives of Pharmacal Research

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Effect of Hepatic Cirrhosis on the Pharmacokinetics of Theophylline in Rats

  • Published : 1997.08.01
Download PDF
⟨ Previous Next ⟩

Abstract

The experimental hepatic cirrhosis was induced either by bile duct ligation (BDL) or by pretreatment with dimethyinitrosamine (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 $(t_{1/2})$ 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 $(8.67{\pm}4.85%)$ decreased about four-folds, but in DMNA $(73.00{\pm}9.85%)$ similar result war 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.

Keywords

References

  1. J. Lab. Clin. Med. v.113 Preventive effect of malotilate on dimethylnitrosamine-in-duced liver fibrosis in the rat Ala Kokko,L.;Stenback,F.;Ryhanen,L.
  2. J. Hepatol. v.13 no.SUP.3 Beneficial effects of inhibitors of prolyl 4-hydroxylase in CCl₄-induced fibrosis of the liver in rats Bickel,M.;Baader,E.;Brocks,D.G.;Engelbart,K.;Guunzler,V.;Schmidts,E.;Vogel,G.H.
  3. J. Hepatol v.13 no.SUP.3 Fibrosis of the liver in rats induced by bile duct ligation : Effcts of inhibition of prolyl 4-hydroxylase Boker,K.;Schwarting,G.;Kaule,G.;Gunzler,V.;Schmidt,E.
  4. Annual report on the cause of death statistics National Statistical Office
  5. J. Pharm. Pharmacol. v.43 Effect of cigarette smoking on theophylline pharmacokinetics in rats Gomita,Y.;Furuno,K.;Eto,K.;Okazaki,M.;Suemaru,K.;Araki,Y.
  6. Biol. Pharm. Bull. v.18 Pharmacokinetics of theophylline : Effects of hepatic fibrosis in rats induced by bile duct ligation Han,S.S.;Kim,K.Y.;Ham,S.H.;Sohn,D.H.;Kim,J.B.
  7. Am. J. Hosp. Pharm. v.34 Absolute bioavailability of oral theophylline Hendeles,L.;Weinberger,M.;Bighley,L.
  8. Anal. Biochem. v.112 A simple method to determine nanogram levels of 4-hydroxyproline in biological tissues Jamall,I.S.;Finelli,V.N.;Que Hee,S.S.
  9. J. Hepatol v.5 A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat Jezequel,A.M.;Mancini,R.;Rinaldesi,M.L.;Macarri,G.;Venturini,C.;Orlandi,F.
  10. Br. J. Exp. Path. v.65 Prolonged bile duct obstruction: a new experimental model for cirrhosis in the rat Kountouras,J.;Billing,B.H.;Scheuer,P.J.
  11. Clin. Pharmacol. Ther. v.29 Theophylline serum protein binding in obstructive airways disease Lesko,L.J.;Tabor,K.J.;Johnson,B.F.
  12. Chest v.73 Pharmacokinetics of theophylline in hepatic disease Mangione,A.;Imhoff,T.E.;Lee,R.V.;Shum,L.Y.;Jusko,W.J.
  13. Clin. Chem. v.23 Microscale method for theophylline in body fluids by reversed-phase high pressure liquid chromatography Orcutt,J.J.;Kozak,P.P.;Gillman,S.A.;Cummins,L.H.
  14. N. Engl. J. Med. v.296 Theophylline disposition in patients with hepatic cirrhosis Piafsky,K.M.;Sitar,D.S.;Rangno,R.E.;Ogilvie,R.I.
  15. N. Engl. J. Med. v.296 Drug disposition in liver disease Shand,D.G.
  16. Applied Biopharmaceutics and Pharmacokinetics(3rd ed.) Shargel,L.;Yu,A.B.C.
  17. Hepatology v.3 Is cirrhosis of the liver experimentally produced by CCI₄an adequate model of human cirrhosis? Tomoya,R.P.
  18. Sem. Liv. Dis. v.10 Experimental model of hepatic fibrosis:a review Tsukamoto,H.;Mathuoka,M.;French,S.W.
  19. Pharmacokinetic Basis for Drug Treatment Effects of hepatic disease on clinical pharmacokinetics Wilkinson,G.R.;Branch,R.A.;Benet,L.Z.(ed.):Massound,N.(ed.);Gambertoglio,J.G.(ed.)
  20. N. Engl. J. Med. v.309 Drug administration in hepatic disease Williams,R.L
  21. J. Pharm. Sci. v.68 Effect of altered plasma protein binding on apparent volume of distribution φie,S.;Tozer,T.N.