Skip to main content
SpringerLink
Log in

Relationship between in vivo and in vitro drug metabolism in man

  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Summary

Relationship between in vivo and in vitro drug metabolism was investigated in 200 consecutive patients with diagnostic liver needle biopsy by comparing the cytochrome P-450 (P-450) content in biopsies with the elimination kinetics of antipyrine. P-450 level in livers varied from 0.5 to 32.5 nmole/g, it was increased in subjects treated with enzyme inducing drugs and reduced in patients with degenerative parenchymal changes in the liver. Antipyrine metabolism also varied markledy, the half-life ranged from 2.2 to 54.4 hrs and the clearance from 3.5 to 142.4 ml/min. Rapid drug metabolism was associated with subjects with normal liver or with slight liver changes in case they were also treated with known inducers whereas reduced antipyrine metabolism was seen in subjects with degenerative liver changes. P-450 content in biopsies was related to the kinetic parameters of antipyrine: correlation between P-450 in livers and the drug clearance was linear whereas a non-linear relationship between P-450 and plasma half-life was obtained. The results demonstrate a relationship between in vivo and in vitro parameters of drug metabolism in man and show the importance of liver parenchymal changes and drug therapy as factors influencing hepatic drug metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vesell, E.S. and Page, J.C. (1968): Genetic control of drug levels in man: Antipyrine. Sceince,161, 72–73.

    CAS  Google Scholar 

  2. Vesell, E.S., Passananti, G.T., Greene, F.E. and Page J.G., 1971. Genetic control of drug levels and of the induction of drug metabolizing enzymes in man. Ann. N. Y. Acad. Sci.,179, 752–761.

    Article  PubMed  CAS  Google Scholar 

  3. Conney, A.H. (1967): Pharmacological implications of microsomal enzyme induction. Pharmacol. Rev.,19, 317–366.

    PubMed  CAS  Google Scholar 

  4. Conney, A.H., Pantuck, E.J., Hsiae, K.G., Kuntzman, R., Alvares, A.P. and Kappas, A. (1977): Regulation of drugs metabolism in man by environmental chemicals and diet. Fed. Proc,36, 1647–1652.

    PubMed  CAS  Google Scholar 

  5. Sotaniemi, E.A. and Huhti, E. (1974): Half-life of intravenous tolbutamide in the serum of patients in medical wards. Ann. Clin. Res.,6, 146–154.

    PubMed  CAS  Google Scholar 

  6. Sotaniemi, E.A., Pelkonen, R.O., Mokka, R.E., Huttunen, R. and Viljakanen, E. (1977): Impairment of drug metabolism in patients with liver cancer. Europ. J. Clin. Invest.,7, 269–274.

    Article  PubMed  CAS  Google Scholar 

  7. Sotaniemi, E.A. (1973): Effects of drug pretieatment on antipyrine levels in blood and tissues: an example of multiple drug interactions. Pharmacology,10, 306–316.

    Article  PubMed  CAS  Google Scholar 

  8. Parke, D.V. (1977): Regulation of the drug-metabolizing enzymes in: Drug metabolism from microbe to man, edited by D.V. Parke and R.L. Smith. Taylor & Francis Ltd, London, p. 55–70.

    Google Scholar 

  9. Orrenius, S. (1977): In vitro systems in the study of drug metabolism and toxicity. International conference on in vivo aspects of biotransformation and toxicity of industrial and environmental xenobiotics. Sept. 13–15, Prague, Czechoslovakia, Abst. 72.

  10. Pelkonen, O., Kaltiala, E.H., Larmi, T.K.I, and Kärki, N.T. (1973): Comparison of activities of drug-metabolizing enzymes in human fetal and adult livers. Clin. Pharm. Ther.,14, 840–846.

    CAS  Google Scholar 

  11. Pelkonen, O., Kaltiala, E.H., Larmi, T.K.I, and Kärki, N.T. (1974): Cytochrome P-450-linked monooxygenase system and drug-induced spectral interactions in human liver microsomes. Chem.-Biol. Interactions,9, 205–216.

    Article  CAS  Google Scholar 

  12. Davies, D.S., Thorgeirsson, S.S., Breckenrigde, A. and Orme, M. (1973): Inter-individual differences in rates of drug oxidation in man. Drug Metab. Disp.,1, 411–417.

    CAS  Google Scholar 

  13. Thorgeirsson, S.S. (1971): Mechanism of hepatic drug oxidation and its relationship to individual differences in rates of oxidation in man. Ph. D. Thesis. University of London.

  14. Davies, D.S. (1977): Drug metabolism in man. Ed. D.V. Parke & R.L. Smith: Drug metabolism from microbe to man. Taylor & Francis Ltd, London, pp. 357–368.

    Google Scholar 

  15. Kalow, W. and Inaba, T. (1976): Genetic factors in hepatic drug oxidation. In progress in liver diseases. New York, San Francisco, London, Grune & Stratton,5, 259–279.

    Google Scholar 

  16. Stevenson, I.H. (1977): Factors influencing antipyrine elimination. Brit. J. Clin. Pharmac.,4, 261–265.

    CAS  Google Scholar 

  17. Remmer, H., Schoene, B., Fleischmann, R.L. and Held, H. (1972): Induction of the unspesific microsomal hydroxylase in human liver. In: The Liver, Quantitative aspects of structure and function, ed. G. Baumgartner & P. Preisig, 232–239, Basel, Karger.

    Google Scholar 

  18. Brodie, B.B. and Axelrod, J. (1950): The fate of antipyrine in man. J. Pharmacol. Exp. Ther.,98, 97–104.

    PubMed  CAS  Google Scholar 

  19. Sotaniemi, E.A., Kontturi, M.J. and Larmi, T.K.I. (1973): Drug metabolism and androgen control therapy in prostatic cancer. Clin. Pharmacol. Ther.,14, 413–417.

    PubMed  CAS  Google Scholar 

  20. Zilly, W., Breimer, D.D. and Richter, E. (1975): Induction of drug metabolism in man following rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. Europ. J. Clin. Pharmacol.,9, 219–227.

    Article  CAS  Google Scholar 

  21. Saarni, H., Sotaniemi, E.A. and Ahokas, J. (1977): Effect of medroxyprogesterone on the hepatic drug metabolism. Acta Pharm. Toxicol.,41, 4, 73.

    Google Scholar 

  22. Ahlqvist, J. (1970): Transverse mounting of ribbons on groups of slides for comparing different stains in adjacent sections. Stein Tech.,45, 38–39.

    CAS  Google Scholar 

  23. Greim, H., Schenkman, M., Klotzbucher, M. and Remmer, H. (1970): The influence of phenobarbital on the turnover of hepatic microsomal cytochrome b5 and cytochrome P-450 in the rat. Biochem. Biophys. acta,201, 20–25.

    PubMed  CAS  Google Scholar 

  24. Prescott, L.F., Adjepon-Yamoak, K.K. and Roberts, E. (1973): Rapid gas-liquid chromatographic estimation of antipyrine in plasma. J. Pharm. Pharmacol.,25, 205–207.

    PubMed  CAS  Google Scholar 

  25. Sherlock, S. Needle biopsy of the liver (1975): In: Diseases of the liver and biliary system. 5th edition, edited by S. Sherlock, Blackwell Scientific Publications, Oxford, London, Edinburgh, Melbourne, 44–54.

    Google Scholar 

  26. Menghini, G. and Ghergo, G.F. (1976): Needle biopsy of the liver. In: Gastroenterology, edited by H.L. Bockus, W. B. Saunders Comp., Philadelphia, London, Toronto,3, 89–112.

    Google Scholar 

  27. Dujovne, C.A. (1977): A clinical pharmacologist’s view of drug hepatotoxicity. Pharm. Res. Comm.,9, 1–15.

    Article  CAS  Google Scholar 

  28. Schoene, F., Fleischmann, P.A., Remmer, H. and von Olderhausen, H.F. (1972): Determination of drug metabolizing enzymes in needle biopsies of human liver. Europ. J. Clin. Pharmacol.,4, 65–73.

    Article  CAS  Google Scholar 

  29. Hepner, G.W. and Vesell, E.S. (1975): Quantitative assessment of hepatic function by breath analysis after oral administration (14-C) aminopyrine. Ann. Intern. Med.,83, 632–638.

    PubMed  CAS  Google Scholar 

  30. Andreasen, P.B., Ranek, L., Statland, R.E. and Tygstrup, N. (1974): Clearance of antipyrine-dependence of quantitative liver function. Europ. J. Clin. Invest.,4, 129–134.

    Article  PubMed  CAS  Google Scholar 

  31. Puistola, U.S. and Sotaniemi, E.A. (1977): Hepatic coma associated with prednisolone treatment of a patient with drug-induced liver damage. Submitted for publication.

  32. Sotaniemi, E.A., Hokkanen, O.T., Ahokas, J.T., Pelkonen, R.O. and Ahlqvist, J. (1977): Hepatic injury and drug metabolism in patients with alpha-metyldopa induced liver damage. Europ. J. Clin. Pharm. In press.

  33. Alvares, A.P., Schilling, G., Levin, W., Kuntzman, R., Brand, L. and Mark, L.C. (1969): Cytochrome P-450 and b5 in human liver microsomes. Clin. Pharm. Ther.,10, 655–659.

    CAS  Google Scholar 

  34. Kapitulnik, J., Levin, W., Lu, A.Y.H., Merecki, R., Dansette, P.M., Jerina, D.M. and Conney, A.H. (1977): Hydration of arene and alkene oxidases by epoxide hydrase in human liver microsomes. Clin. Pharm. Ther.,21, 158–165.

    CAS  Google Scholar 

  35. Kapitulnik, J., Poppers, P.J. and Conney, A.H. (1977): Comparative metabolism of benzo (a) pyrene and drugs in human liver. Clin. Pharm. Ther.,21, 166–176.

    CAS  Google Scholar 

  36. Wilkinson, G.R. and Shand, D.G. (1975): A physiological approach to hepatic drug clearance. Clin. Pharmacol. Ther.,18, 377–390.

    PubMed  CAS  Google Scholar 

  37. Wilkinson, G.R. and Schenker, S. (1976): Effects of liver disease on drug disposition in man. Biochem. Pharmacol.,25, 2675–2681.

    Article  PubMed  CAS  Google Scholar 

  38. Cohn, J.M., Khatri, J.M., Groszmann, R.J. and Kotelanski, B. (1972): Hepatic blood flow in alcoholic liver disease measured by an indicator dilutor technique. Amer. J. Med.,53, 704–714.

    Article  PubMed  CAS  Google Scholar 

  39. Groszmann, R., Kotelanski, B., Cohn, J.N. and Khatri, J.M. (1972): Quantitation of portosystemic shunting from the splenic and mesenteric beds in alcoholic liver disease. Amer. J. Med.,53, 715–722.

    Article  PubMed  CAS  Google Scholar 

  40. Groszmann, R.J., Kraveta, D. and Parysow, O. (1977): Intrahepatic arteriovenous shunting in cirrhosis of the liver. Gastroenterology,73, 201–204.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clin. Res. Unit., Dept. of Internal Medicine, University of Oulu, SF-90220, Oulu, 22, Finland

    Eero A. Sotaniemi M.D. (Ass. Prof.) & Heikki I. Pirttiaho

  2. Department of Pharmacology, University of Oulu, SF-90220, Oulu, 22, Finland

    R. Olavi Pelkonen & Jorma T. Ahokas

  3. Department of Pathology, Aurora Hospital, Helsinki, Finland

    Johan Ahlqvist

Authors
  1. Eero A. Sotaniemi M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Olavi Pelkonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jorma T. Ahokas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heikki I. Pirttiaho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Johan Ahlqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sotaniemi, E.A., Pelkonen, R.O., Ahokas, J.T. et al. Relationship between in vivo and in vitro drug metabolism in man. European Journal of Drug Metabolism and Pharmacokinetics 3, 39–45 (1978). https://doi.org/10.1007/BF03189367

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03189367

Key words

Search

Navigation