Time-dependent kinetics of lignocaine in the isolated perfused rat liver

  • M. S. Lennard
  • G. T. Tucker
  • H. F. Woods


The kinetics of lignocaine have been investigated in the isolated perfused rat liver preparation. After a low dose (0.3 mg) the drug was eliminated according to first-order kinetics, but after higher doses (7.5, 15.0 mg) and multiple doses (3×1.5 mg at 15 min intervals), nonlinear kinetics were observed, which appeared to show time dependence. This was not due to deterioration of the preparation nor was there any evidence of a hepatotoxic effect of lignocaine. The kinetics of lignocaine were also found to be sex-dependent since it was eliminated at a faster rate by livers from male rats compared to those from female rats. Exogenous MEGX (7.5 mg), the mono-N-deethylated metabolite of lignocaine, inhibited the elimination of parent drug (1.5 mg dose). However, evidence was obtained suggesting that a direct effect of this and other end-product metabolites may not be responsible for the observed changes in lignocaine kinetics with time when the compounds are produced endogenously. Studies of the hepatic binding of lignocaine in the preparation showed the presence of high affinity-low capacity and low affinity-high capacity binding sites, which may be the enzymes responsible for aromatic hydroxylation and N-deethylation of the drug, respectively. Further experiments supported the view that an intermediate product of lignocaine, related to the N-deethylation pathway, might be inhibiting its further metabolism.

Key words

zlignocaine lidocaine time-dependent kinetics isolated perfused rat liver nonlinear hepatic uptake 


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  1. 1.
    L. F. Prescott, K. K. Adjepon-Yamoah, and R. G. Talbot. Impaired lignocaine metabolism in patients with myocardial infarction.Br. Med. J. 1:939–941 (1976).PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    J. Le Lorier, J. D. Grenon, Y. Latour, G. Caille, G. Dumont, A. Brosseau, and A. Solignac. Pharmacokinetics of lidocaine after prolonged intravenous infusion in uncomplicated myocardial infarction.Ann. Intern. Med,87:700–702 (1977).CrossRefGoogle Scholar
  3. 3.
    R. L. Nation, E. G. Triggs, and M. Selig. Lidocaine kinetics in cardiac and aged subjects.Br. J. Clin. Pharmacol. 4:439–448 (1977).PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    N. D. S. Bax, G. T. Tucker, and H. F. Woods. Lignocaine and indocyanine green kinetics in patients following myocardial infarction.Br. J. Clin. Pharmacol. 10:353–361 (1980).PubMedCentralPubMedGoogle Scholar
  5. 5.
    P. A. Routledge, W. W. Stargel, G. S. Wagner, and D. G. Shand. Increased alpha-1-acid glycoprotein and lidocaine disposition in myocardial infarction.Ann. Intern. Med. 93:701–704 (1980).PubMedCrossRefGoogle Scholar
  6. 6.
    H. R. Ochs, G. Carstens, and D. J. Greenblatt. Reduction in lidocaine clearance during continuous infusion and by coadministration of propranolol.N. Engl. J. Med. 303:373–377 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    G. T. Tucker, L. Wiklund, A. Berlin-Wahlen, and L. E. Mather. Hepatic clearance of local anaesthetics.J. Pharmacokin. Biopharm. 5:111–122 (1977).CrossRefGoogle Scholar
  8. 8.
    J. Le Lorier, R. Moison, J. Gagne, and G. Caille. Effect of duration of infusion on the disposition of lidocaine in dogs.J. Pharmacol. Exp. Ther. 203:507–511 (1977).Google Scholar
  9. 9.
    N. Vicuna, D. Lalka, S. R. Burrow, A. J. Maclean, P. du Souich, and J. L. McNay. Dose-dependent pharmacokinetic behavior of lidocaine in the conscious dog.Res. Commun. Chem. Pathol. Pharmacol. 22:485–492 (1978).PubMedGoogle Scholar
  10. 10.
    L. A. Bauer, T. Brown, M. Gibaldi, L. Hudson, S. Nelson, V. Raisys, and J. P. Shea. Influence of long-term infusions on lidocaine kinetics.Clin. Pharmacol. Ther. 31:433–437 (1982).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Hems, B. D. Ross, M. N. Berry, and H. A. Krebs. Gluconeogenesis in the perfused rat liver.Biochem. J. 101:284–292 (1966).PubMedCentralPubMedGoogle Scholar
  12. 12.
    H. A. Krebs and K. Henseleit. Untersuchungen über die Harnstoffbildung im Tierkörper.Hoppe-Seyler's Z. Physiol. Chem. 210:33–66 (1932).CrossRefGoogle Scholar
  13. 13.
    A. Wollenberger, O. Ristau, and G. Schoffa. Eine einfache Technik der extrem schnellen Abkühlung gröserer Gewebestücke.Pflügers Arch. Ges. Physiol. 270:399–412 (1960).CrossRefGoogle Scholar
  14. 14.
    H. B. Hucker and S. C. Stauffer. G.I.c. analysis of lidocaine in plasma using a novel nitrogen-sensitive detector.J. Pharm. Sci. 65:926–927 (1976).PubMedCrossRefGoogle Scholar
  15. 15.
    R. L. Nation, E. J. Triggs, and M. Selig. Gas Chromatographic method for the quantitative determination of lidocaine and its metabolite monoethylglycinexylidide in plasma.J. Chromatogr. 116:188–193 (1976).PubMedCrossRefGoogle Scholar
  16. 16.
    H. U. Bergmeyer, E. Bernt, F. Schmidt, and H. Stork. D-Glucose: determination with hexokinase and glucose-6-phosphate dehydrogenase. InMethods of Enzymatic Analysis, H. U. Bergmeyer (ed.). Academic Press, New York, 1974, pp. 1196–1210.Google Scholar
  17. 17.
    K. S. Pang and M. Rowland. Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel-tube” model using lidocaine in the perfused rat liverin situ preparation.J. Pharmacokin. Biopharm. 5:655–679 (1977).CrossRefGoogle Scholar
  18. 18.
    H. A. Krebs, R. A. Freedland, R. Hems, and M. Stubbs. Inhibition of hepatic gluconeogenesis by ethanol.Biochem. J. 112:117–124 (1969).PubMedCentralPubMedGoogle Scholar
  19. 19.
    H. E. Rosenthal. A graphic method for the determination and presentation of binding parameters in a complex system.Anal. Biochem. 20:525–532 (1967).PubMedCrossRefGoogle Scholar
  20. 20.
    G. Nyberg, B. Karlen, I. Hedlund, R. Grundin, and C. von Bahr. Extraction and metabolism of lidocaine in rat liver.Acta Pharmacol. Toxicol. 40:337–346 (1977).CrossRefGoogle Scholar
  21. 21.
    C. von Bahr, I. Hedlund, B. Karlen, D. Backström, and H. Grasdalen. Evidence for two catalytically different binding sites of liver microsomal cytochrome P-450: Importance for species and sex differences in oxidation pattern for lidocaine.Acta Pharmacol. Toxicol. 41:39–48 (1977).CrossRefGoogle Scholar
  22. 22.
    R. G. Thurman and R. Scholz. Mixed function oxidation in the perfused rat liver. The effect of aminopyrine on oxygen uptake.Eur. J. Biochem. 10:459–467 (1969).PubMedCrossRefGoogle Scholar
  23. 23.
    R. G. Thurman, D. P. Marrazzo, L. S. Jones, and F. C. Kauffman. The continuous kinetic determination of p-nitroanisole O-demethylation in hemoglobin-free perfused rat liver.J. Pharmacol. Exp. Ther. 201:498–506 (1977).PubMedGoogle Scholar
  24. 24.
    J. B. Keenaghan and R. N. Boyes. The tissue distribution, metabolism and excretion of lidocaine in rats, guinea pigs, dogs and man.J. Pharmacol. Exp. Ther. 180:454–463 (1972).PubMedGoogle Scholar
  25. 25.
    K. S. Pang and M. Rowland. Hepatic clearance of drugs. III. Additional experimental evidence supporting the “well-stirred” model, using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liverin situ preparation.J. Pharmacokin. Biopharm. 5:681–699 (1977).CrossRefGoogle Scholar
  26. 26.
    M. R. Franklin. Inhibition of mixed function oxidations by substrates forming reduced cytochrome P-450 metabolic-intermediate complexes.Pharmacol. Ther. 2:227–245 (1977).Google Scholar
  27. 27.
    J. F. Pritchard, D. W. Schneck, and A. H. Hayes. The inhibition of rat hepatic microsomal propranolol metabolism by a covalently bound reactive intermediate.Res. Commun. Chem. Pathol. Pharmacol. 27:211–222 (1980).PubMedGoogle Scholar
  28. 28.
    G. H. Evans, G. R. Wilkinson, and D. G. Shand. The disposition of propranolol. IV. A dominant role for tissue uptake in the dose-dependent extraction of propranolol by the perfused rat liver.J. Pharmacol. Exp. Ther. 186:447–454 (1973).PubMedGoogle Scholar
  29. 29.
    D. G. Shand, R. A. Branch, G. H. Evans, A. S. Nies, and G. R. Wilkinson. The disposition of propranolol. VII. The effects of saturable hepatic tissue uptake on drug clearance by perfused rat liver.Drug Metab. Dispos. 1:679–686 (1973).PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1983

Authors and Affiliations

  • M. S. Lennard
    • 1
  • G. T. Tucker
    • 1
  • H. F. Woods
    • 1
  1. 1.University Department of TherapeuticsRoyal Hallamshire HospitalSheffieldUK

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