Skip to main content
SpringerLink
Log in

Measurement of hepatic drug-metabolizing enzyme activity in man

Comparison of three different assays

  • Originals
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Summary

Three parameters of hepatic drug metabolism, cytochrome P-450 (P-450) content, antipyrine metabolism and urinary excretion of glucaric acid (GA) were investigated in 161 patients who underwent diagnostic liver needle biopsy. P-450 and antipyrine metabolism, but not GA were related to histological changes in liver. All the parameters were significantly increased in subjects treated with enzyme-inducing drugs, the extent of induction being related to alterations in liver histology. The largest responses were seen in subjects with an intact liver and the smallest in those with hepatitis or cirrhosis. Therapy with inducers partly compensated for the impairement in drug metabolism caused by the disease process; thus, some patients with altered liver had normal values in the tests if they had been treated with inducers. There were significant correlations between in vivo and in vitro parameters of drug metabolism, but in the interpretation of data selection of the material and the parameters influenced the results. Thus, the antipyrine plasma clearance rate was directly related to P-450 and GA values, whereas the correlation between the latter and the drug half-life was non-linear. Also, comparison of selected groups of patients resulted in better correlations between the indices of drug metabolism than in the entire series. The results demonstrate that the overall picture of hepatic drug metabolism in man is largely determined by histological changes in the liver and by exposure to drugs, which are reflected differently in various assays of hepatic drug metabolism. Quantitative evaluation of these factors, and selection of the appropriate assay method, seem to be of importance in investigating hepatic drug metabolism in man.

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. Aarts EM (1965) Evidence for the function of D-glucaric acid as an indicator for drug induced enhanced metabolism through the glucuronic acid pathway in man. Biochem Pharmacol 14: 359–363

    Google Scholar 

  2. Ahlqvist J (1970) Transverse mounting of ribbons on groups of slides for comparing different stains in adjacent sections. Stain Technol 45: 38–39

    Google Scholar 

  3. Alvares AP, Schilling G, Lewin W, Kuntzman R, Brand L, Mark LC (1969) Cytochrome P-450 and b5 in human liver microsomes. Clin Pharmacol Ther 10: 655–659

    Google Scholar 

  4. Andreasen PB, Ranek L, Statland RE, Tygstrup N (1974) Clearance of antipyrine-dependence of quantitative liver function. Eur J Clin Invest 4: 129–134

    Google Scholar 

  5. von Bahr C, Björken C, Groth C-G, Jansson H, Kager L, Lind M, Lundgren G, Glaumann H (1978) Drug metabolism in human liver in vitro. Establishment of a human “liver bank”. 7th International Congress on Pharmacology, Paris, July 16–21 Abst. N 1013

  6. Branch RA, Herbert CM, Read AF (1973) Determinants of serum antipyrine half-lives in patients with liver disease. Gut 14: 569–573

    Google Scholar 

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

    Google Scholar 

  8. Brodie BB, Burns JJ, Weiner M (1959) Metabolism of drugs in subjects with Laennes's cirrhosis. Med Exp 1: 290–292

    Google Scholar 

  9. Conney AH (1967) Pharmacological implications of microsomal enzyme induction. Pharmacol Rev 19: 317–366

    Google Scholar 

  10. Cunningham JL, Prince Evans DA (1974) Urinary D-glucaric acid excretion and acetanilide pharmacokinetics before and during diphenylhydantoin administration. Eur J Clin Pharmacol 7: 387–391

    Google Scholar 

  11. Davis M, Simmons CJ, Dordoni B, Williams R (1974) Urinary D-glucaric excretion and plasma antipyrine kinetics during enzyme induction. Br J Clin Pharmacol 1: 253–257

    Google Scholar 

  12. Davies DS (1977) Drug metabolism in man. In: Parke DV, Smith RL (eds). Drug metabolism from microbe to man. Tayler & Francis, London, pp 357–368

    Google Scholar 

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

    Google Scholar 

  14. Hepner GW, Vesell ES (1975) Quantitative assessment of hepatic function by breath analysis after oral administration of (14C) aminopyrine. Ann Int Med 83: 632–628

    Google Scholar 

  15. Hunter J, Carerella M, Maxwell JD, Stewart DA, Williams R (1971) Urinary D-glucaric -acid excretion as a test for hepatic enzyme induction in man. Lancet 1: 572–575

    Google Scholar 

  16. Hunter J (1974) Enzyme induction and medical treatment. J R Coll Physicians London 8: 163–174

    Google Scholar 

  17. Hunter J, Maxwell JD, Stewart DA, Williams R (1973) Urinary D-glucaric acid excretion and total liver content of cytochrome P-450 in guinea pigs: relationship during enzyme induction and following inhibition of protein synthesis. Biochem Pharmacol 22: 743–747

    Google Scholar 

  18. Kalow W, Inaba T (1976) Genetic factors in hepatic drug oxidations. In: Popper H, Schaffner F (eds) Progress in liver disease, Vol. 5. Grune & Stratton, New York, pp 246–258

    Google Scholar 

  19. Kapitulnik J, Poppers PJ, Conney AH (1977) Comparative metabolism of benzo(a)pyrene and drugs in human liver. Clin Pharmacol Ther 21: 166–176

    Google Scholar 

  20. Klotz U, McHorse TS, Wilkinson GR (1974) The effect of cirrhosis on the disposition and elimination of meperidine (pethidine) in man. Clin Pharmacol Ther 16: 667–675

    Google Scholar 

  21. Koch-Weser J (1972) Drug therapy. Serum drug concentrations as therapeutic guides. N Engl J Med 287: 227–231

    Google Scholar 

  22. Lancet (1974) Drug metabolism in disease Lancet 1: 790–791

    Google Scholar 

  23. Latham AN, Turner P, Franklin C, Maclay W (1974) Phenobarbitone-induced urinary excretion of D-glucaric acid and 6-beta-hydroxycortisol on man. Can J Physiol Pharmacol 54: 778–782

    Google Scholar 

  24. Lecamwasam DS, Franklin C, Turner P (1975) Effect of phenobarbitone on hepatic drug-metabolizing enzymes and urinary D-glucaric acid excretion in man. Br J Clin Pharmacol 2: 257–262

    Google Scholar 

  25. Marsh CA (1963) Metabolism of D-glucuronolactone in mammalian systems. Biochem J 86: 77–86

    Google Scholar 

  26. Marsh CA, Carr AJ (1965) Changes in enzyme activity, related to D-glucaric acid synthesis, with age, pregnancy and malignancy. Clin Sci 28: 209–217

    Google Scholar 

  27. Mawer GE, Miller WE, Turnberg LA (1972) Metabolism of amylobarbitone in patients with chronic liver disease. Br J Pharmacol 44: 549–560

    Google Scholar 

  28. Pelkonen O, Kaltiala EH, Larmi TKI, Kärki NT (1973) Comparison of activities of drug-metabolizing enzymes in human fetal and adult liver. Clin Pharmacol Ther 14: 840–846

    Google Scholar 

  29. Prescott LF, Adjepon-Yamoah KK, Roberts E (1973) Rapid gas-liquid chromatographic estimation of antipyrine in plasma. J Pharm Pharmacol 25: 205–207

    Google Scholar 

  30. Remmer H, Schoene B, Fleischmann RL, Held H (1972) Induction of unspecific microsomal hydroxylase in human liver. In: Baumgartner G, Preisig P (eds) The liver. Quantitative aspects of structure and function. Karger, Basel, pp 232–239

    Google Scholar 

  31. Schoene B, Fleischman RA, Remmer H, von Olderhausen HF (1973) Determination of drug metabolizing enzymes in needle biopsies of human liver. Eur J Clin Pharmacol 4: 65–73

    Google Scholar 

  32. Smith SE, Rawlins MD (1974) Prediction of drug oxidation rates in man: lack of correlation with serum gamma-glutamyl transpeptidase, urinary excretion of D-glucaric acid and 6-beta-hydroxycortisol. Eur J Clin Pharmacol 7: 71–75

    Google Scholar 

  33. Sotaniemi EA, Medzihradsky F, Eliasson G (1974) Glucaric acid as an indicator of use of enzyme-inducing drugs. Clin Pharmacol Ther 15: 417–423

    Google Scholar 

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

    Google Scholar 

  35. Sotaniemi EA, Pelkonen RO, Mokka RE, Huttunen R, Viljakainen E (1977) Impairment of drug metabolism in patients with liver cancer. Eur J Clin Invest 7: 269–274

    Google Scholar 

  36. Sotaniemi EA, Pelkonen RO, Ahokas JT, Pirttiaho HI, Ahlqvist J (1978) Relationship between in vivo and in vitro drug metabolism in man. Eur J Drug Metab Pharmacokinet 3: 39–45

    Google Scholar 

  37. Sotaniemi EA, Hynynen T, Ahlqvist J, Ahokas JT, Puoskari U, Pelkonen I (1978) Effects of medroxyprogesterone on the liver function and drug metabolism of patients with primary biliary cirrhosis and chronic active hepatitis. J Med 9: 117–128

    Google Scholar 

  38. Sotaniemi EA, Anttila M, Pelkonen RO, Järvensivu P, Sunquist H (1979) Plasma clearance of propranolol and sotalol in relation to hepatic drug-metabolizing enzyme activity. Clin Pharmacol Ther 26: 155–161

    Google Scholar 

  39. Stevenson IH (1977) Factors influencing antipyrine elimination. Br J Clin Pharmacol 4: 261–265

    Google Scholar 

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Clinical Research Unit, University of Oulu, Finland

    E. A. Sotaniemi

  2. Departments of Internal Medicine and Pharmacology, University of Oulu, Finland

    R. O. Pelkonen

  3. Department of Clinical Chemistry, University of Oulu, Finland

    M. Puukka

Authors
  1. E. A. Sotaniemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. O. Pelkonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Puukka
    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. & Puukka, M. Measurement of hepatic drug-metabolizing enzyme activity in man. Eur J Clin Pharmacol 17, 267–274 (1980). https://doi.org/10.1007/BF00625800

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00625800

Key words

Search

Navigation