, Volume 50, Issue 1, pp 21–27 | Cite as

Comparison of single dose kinetics of imipramine, nortriptyline and antipyrine in man

  • Lars F. Gram
  • Per Buch Andreasen
  • Kerstin Fredricson Overø
  • Johannes Christiansen
Human Pharmacology Original Investigations


The single dose kinetics of imipramine (IP), nortriptyline (NT), and antipyrine (AP) were compared in 7 healthy subjects. Test doses of AP were given intravenously and test doses of IP and NT were given both orally and by intravenous infusion. The plasma concentration/time curves after intravenous IP and NT were analysed according to a 2-compartment open model. In addition a blood flow independent ‘true’ clearance was calculated according to a sinusoidal perfusion model. Indirect estimates of hepatic blood flow were obtained from the oral and i.v. plasma concentration/time curves after NT administration.

Compared to NT, IP had statistically significant higher clearances, shorter half-lives, and smaller apparent volumes of distribution. There was a significant correlation between apparent volume of distribution (Vdβ) of IP and NT (n=5,r=0.85), but only a weak correlation between the clearance measurements of the two compounds. Systemic clearance of AP and IP showed some positive correlation (n=7,r=0.73), whereas there were no significant correlations between AP and NT kinetics.

The data indicate that inter- and intraindividual variations in hepatic blood flow may influence the measurements. Other possible sources of variability are individual differences in hepatic extraction kinetics, and differences in binding to blood constitutents.

Key words

Imipramine Nortriptyline Antipyrine Single-dose Kinetics 


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  1. Alexanderson, B.: Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses. A cross-over study. Europ. J. clin. Pharmacol.5, 1–10 (1972)Google Scholar
  2. Alexanderson, B., Borgå, O.: Interindividual differences in plasma protein binding of nortriptyline in man—A twin study. Europ. J. clin. Pharmacol.4, 196–200 (1972)Google Scholar
  3. Alexanderson, B., Borgå, O., Alván, G.: The availability of orally administered nortriptyline. Europ. J. clin. Pharmacol.5, 181–185 (1973)Google Scholar
  4. Andreasen, P. B., Vesell, E. S.: Comparison of plasma levels of antipyrine, tolbutamide and warfarin after oral and intravenous administration. Clin. Pharmacol. Ther.16, 1059–1065 (1974)Google Scholar
  5. Bahr, C. von: Spectral studies on the interaction of imipramine and some of its oxidized metabolites with rat liver microsomes. Xenobiotica1, 69–78 (1971)Google Scholar
  6. Bahr, C. von: Binding and oxidation of amitriptyline and a series of its oxidized metabolites in liver microsomes from untreated and phenobarbital-treated rats. Xenobiotica2, 293–306 (1972)Google Scholar
  7. Bass, L., Keiding, S., Winkler, K., Tygstrup, N.: Enzymatic elimination of substrates flowing rhough the intact liver. J. theor. Biol. (in press)Google Scholar
  8. Bickel, M. H.: Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood compounds. J. Pharm. Pharmacol.27, 733–738 (1975)Google Scholar
  9. Bickel, M. H., Steele, J. W.: Binding of basic and acidic drugs to rat tissue subcellular fractions. Chem. Biol. Interact.8, 151–162 (1974)Google Scholar
  10. Borgå, O., Azarnoff, D. L., Forshell, G. P., Sjöqvist, F.: Plasma protein binding of tricyclic antidepressants in man. Biochem. Pharmacol.18, 2135–2143 (1969)Google Scholar
  11. Brien, J. F., Inaba, T., Kalow, W.: Comparative drug elimination in man—diphenylhydantoin and amobarbital. Europ. J. clin. Pharmacol.9, 79–83 (1975)Google Scholar
  12. Brodie, B. B., Axelrod, J., Sokerman, R., Levy, B. B.: The estimation of antipyrine in biological materials. J. biol. Chem.179, 25–29 (1949)Google Scholar
  13. Campbell, I. C., Todrick, A.: Plasma protein binding of tricyclic antidepressive drugs. J. Pharm. Pharmacol.22, 226 (1970)Google Scholar
  14. Collinsworth, K. A., Strong, J. M., Atkinson, A. J., Winkle, R. A., Perlroth, F., Harrison, D. C.: Pharmacokinetics and metabolism of lidocaine in patients with renal failure. Clin. Pharmacol. Ther.18, 59–64 (1975)Google Scholar
  15. Curry, S.: Relation between binding to plasma protein, apparent volume of distribution, and rate constants of disposition and elimination for chlorpromazine in three species. J. Pharm. Pharmacol.24, 818–819 (1972)Google Scholar
  16. Davies, D. S., Thorgeirsson, S. S.: Individual differences in the plasma half lives of lipid soluble drugs in man. Acta pharmacol. (Kbh.)29, Suppl. 3, 182–190 (1971)Google Scholar
  17. Davies, D. S., Thorgeirsson, S. S., Breckenridge, A., Orme, M.: Interindividual differences in rates of drug oxidation in man. Drug Metab. Disp.1, 411–417 (1973)Google Scholar
  18. Fredericson Overø, K.: Increased specificity of the3H-acetic anhydride coupling method for plasma analysis of drugs containing secondary amino groups. Acta pharmacol. (Kbh.)31, 433–440 (1972)Google Scholar
  19. Fredericson Overø, K., Gram, L. F., Hansen, V.: Kinetics of nortriptyline in man according to a two compartment model. Europ. J. clin. Pharmacol.8, 343–347 (1975)Google Scholar
  20. Gram, L. F., Christiansen, J.: First-pass metabolism of imipramine in man. Clin. Pharmacol. Ther.17, 555–563 (1975)Google Scholar
  21. Gram, L. F., Fredricson Overø, K.: First-pass metabolism of nortriptyline in man. Clin. Pharmacol. Ther.18, 305–314 (1975)Google Scholar
  22. Gram, L. F., Kofod, B., Christiansen, J., Rafaelsen, O. J.: Drug Interaction: Inhibitory effect of neuroleptics on metabolism of tricyclic antidepressants in man. In: O. Vinar, Z. Votava, and P. B. Bradly, eds. Advances in Neuropsychopharmacology. Proc. VI Congr. Collegium Internationale Neuro-Psychopharmacologium, Prague 1970, pp. 447–452 Amsterdam: North-Holland 1971bGoogle Scholar
  23. Gram, L. F., Kofod, B., Christiansen, J., Rafaelsen, O. J.: Imipramine metabolism, pH dependent distribution and urinary excretion. Clin. Pharmacol. Ther.12, 239–244 (1971a)Google Scholar
  24. Gram, L. F., Reisby, N., Ibsen, I., Nagy, A., Dencker, S. J., Bech, P., Petersen, G. O., Christiansen, J.: Plasma levels and antidepressive effect of imipramine. Clin. Pharmacol. Ther.19, 318–324 (1976)Google Scholar
  25. Greisen, G., Andreasen, P. B.: Two compartment analysis of plasma elimination of phenazone in normals and in patients with cirrhosis of the liver. Acta pharmacol. (Kbh.)38, 49–58 (1976)Google Scholar
  26. Hammer, W. M., Brodie, B. B.: Application of isotope derivative technique to assay of secondary amines: Estimation of desipramine by acetylation with H3-acetic anhydride. J. Pharmacol. exp. Ther.157, 503–508 (1967)Google Scholar
  27. Hammer, W. M., Märtens, S., Sjöqvist, F.: A comparative study of the metabolism of desmethylimipramine, nortriptyline and oxyphenylbutazone in man. Clin. Pharmacol. Ther.10, 44–49 (1969)Google Scholar
  28. Jørgensen, A., Staehr, P.: On the biological half-life of amitriptyline. J. Pharm. Pharmacol.28, 62–64 (1976)Google Scholar
  29. Kadar, D., Inaba, T., Endrenyi, L., Johnson, G. E., Kalow, W.: Comparative drug elimination capacity in man—glutethimide, amobarbital, antipyrine, and sulfinpyrazone. Clin. Pharmacol. Ther.14, 552–560 (1973)Google Scholar
  30. Keiding, S.: Hepatic elimination kinetics; the influence of hepatic blood flow on clearance determination. Scan. J. clin. Lab. Invest.36, 113–118 (1976)Google Scholar
  31. Nagy, A., Johansson, R.: Plasma levels of imipramine and desipramine in man after different routes of administration. Naunyn-Schmiedeberg's Arch. Pharmacol290, 145–160 (1975)Google Scholar
  32. Nagy, A., Treiber, L.: Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thinlayer chromatograms. J. Pharm. Pharmacol.25, 599–603 (1973)Google Scholar
  33. Rowland, M., Benet, L. Z., Graham, G. G.: Clearance concepts in pharmacokinetics. J. Pharmacokinet. Biopharm.1, 123–136 (1973)Google Scholar
  34. Shand, D. G., Rangno, R. E.: The disposition of propranolol I. Elimination during oral absorption in man. Pharmacology7, 159–168 (1972)Google Scholar
  35. Sjöqvist, F., Bahr, C. von: Interindividual differences in drug oxidation: Clinical importance. Drug Metab. Disp.1, 469–482 (1973)Google Scholar
  36. Smith, S. E., Rawlins, M. D.: Prediction of drug oxidative rates in man: Lack of correlation with gammaglutamyl transpeptidase and urinary excretion of d-glycaric acid and 6-hydroxycortisol. Europ. J. clin. Pharmacol.7, 71–75 (1974)Google Scholar
  37. Swartz, R. D., Sidell, F. R., Cucinell, S. A.: Effects of physical stress on the disposition of drugs eliminated by the liver in man. J. Pharmacol. exp. Ther.188, 1–7 (1974)Google Scholar
  38. Vesell, E. S., Page, J. G.: Genetic control of dicumarol levels in man. J. clin. Invest.47, 2657–2663 (1968)Google Scholar
  39. Vesell, E. S., Passanati, G. T., Glenwright, P. A., Dvorchik, B. H.: Studies on the disposition of antipyrine, aminopyrine and phenacetin using plasma, saliva and urine. Clin. Pharmacol. Ther.18, 259–272 (1975)Google Scholar
  40. Wilkinson, G. R., Shand, D. G.: Presystemic hepatic elimination. Acta Pharm. Suec.11, 648–649 (1974)Google Scholar
  41. Wilkinson, G. R., Shand, D. G.: A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther.18, 377–390 (1975)Google Scholar

Copyright information

© Springer-Verlag 1976

Authors and Affiliations

  • Lars F. Gram
    • 1
  • Per Buch Andreasen
    • 2
  • Kerstin Fredricson Overø
    • 3
  • Johannes Christiansen
    • 4
  1. 1.Department of PharmacologyUniversity of CopenhagenCopenhagen ØDenmark
  2. 2.Division of Hepatology, Medical Department A, RigshospitaletUniversity of CopenhagenCopenhagenDenmark
  3. 3.Research LaboratoriesH. Lundbeck & Co. Ltd.CopenhagenDenmark
  4. 4.Department of Clinical Chemistry A, RigshospitaletUniversity of CopenhagenCopenhagenDenmark

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