Drug pharmacokinetics and the carbon dioxide breath test

  • Elizabeth A. Lane
  • Ioanis Parashos


The interrelationship of the pharmacokinetics of a drug and the expiration of carbon dioxide formed as a metabolite have been studied. The pharmacokinetic characteristics of the drug that affect the usefulness of the carbon dioxide excretion as a measure of liver function were examined by means of computer simulations. The parent drug extraction ratio, fraction demethylated, volume of distribution, and absorption rate of an oral dosage form all contribute to the carbon dioxide breath test result. A drug that would be a useful substrate when the carbon dioxide breath test is used as a probe for changes in liver function should be at least 50% metabolized by demethylation, have a hepatic extraction ratio of 0.2–0.5, and be administered in a form that is rapidly absorbed.

Key words

carbon dioxide breath test pharmacokinetics metabolite extraction ratio aminopyrine caffeine 

Appendix b. symbols


net clearance of formaldehyde to carbon dioxide


intrinsic hepatic clearance of formation of formaldehyde from parent drug (bound and unbound to plasma proteins)


intrinsic hepatic clearance of total parent drug (bound and unbound to plasma proteins)


systemic hepatic clearance of formation of formaldehyde from parent drug,QHCLint,f/(QH +CLint,p)


systemic hepatic clearance of parent drug,QHCLint,p/(QH +CLint,p)


extraction ratio,CLint,p/(QH +CLint,p


fraction escaping first-pass metabolism,QH/(QH +CLint,p


fraction of parent drug metabolized by demethylation to formaldehyde,CLint,f/CLint,p


amount of formaldehyde


concentration of formaldehyde


absorption rate constant


metabolite of P formed by routes other than demethylation


metabolite of P formed by demethylation


amount of parent drug in the body


concentration of parent drug measured in arterial blood


amount of parent drug at absorption site


amount of parent drug in the liver


hepatic blood flow


volume of distribution of formaldehyde


volume of distribution of parent drug


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    A. F. Hofmann and B. H. Lauterburg. Breath test with isotopes of carbon: Progress and potential.J. Lab. Clin. Med. 90:405–411 (1977).PubMedGoogle Scholar
  2. 2.
    B. H. Lauterburg and J. Bircher. Expiratory measurement of maximal aminopyrine demethylationin vivo. Effect of phenobarbital, partial hepatectomy, portacaval shunt and bile duct ligation in the rat.J. Pharmacol. Exp. Theor. 196:501–509 (1976).Google Scholar
  3. 3.
    G. W. Hepner and E. S. Vesell. Quantitative assessment of hepatic function by breath analysis after oral administration of14 C-aminopyrine.Ann. Inter. Med. 83:632–638 (1975).CrossRefGoogle Scholar
  4. 4.
    E. Renner, H. Wietholtz, P. Huguenin, M. J. Arnaud, and R. Preisig. Caffeine: A model compound for measuring liver function.Hepatology 4:38–46 (1984).PubMedCrossRefGoogle Scholar
  5. 5.
    A. N. Kotake, D. A. Schoeller, G. H. Lambert, A. L. Baker, D. D. Schaffer, and H. Josephs. The caffeine CO2 breath test: Dose response and route ofN-demethylation in smokers and nonsmokers.Clin. Pharmacol. Ther. 32:261–269 (1982).PubMedCrossRefGoogle Scholar
  6. 6.
    H. Wietholtz, M. Voegelin, M. J. Arnaud, J. Bircher, and R. Preisig. Assessment of the cytochrome P-448 dependence liver enzyme system by a caffeine breath test.Eur. J. Clin. Pharmacol. 21:53–59 (1981).PubMedCrossRefGoogle Scholar
  7. 7.
    K. J. Breen, R. W. Bury, I. V. Calder, P. V. Desmond, M. Peters, and M. L. Mashford. A [14C] phenacetin breath test to measure hepatic function in man.Hepatology 4:47–52 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    J. Fahl, W. Wong, P. D. Klein, and J. B. Watkins.13CO2-methacetin breath test for hepatic function—A noninvasive approach.Hepatology 4:1094 (1984).Google Scholar
  9. 9.
    J. Fahl, R. Kaplan, D. Antonow, W. Wong, P. D. Klein, R. Soloway, and J. B. Watkins.13CO2-methacetin breath test: A comparative analysis.Hepatology 4:1094 (1984).Google Scholar
  10. 10.
    G. W. Hepner, E. S. Vesell, A. Lipton, H. A. Harvey, G. R. Wilkinson, and S. Schenker. Disposition of aminopyrine, diazepam and indocyanine green in patients with liver disease or on anticonvulsant therapy: Diazepam breath test and correlation in drug elimination.J. Lab. Clin. Med. 90:440–456 (1976).Google Scholar
  11. 11.
    G. W. Hepner and E. S. Vesell. Assessment of aminopyrine metabolism in man by breath analysis after oral administration of14C-aminopyrine. Effects of phenobarbital, disulfiram and portal cirrhosis.N. Engl. J. Med. 29:1384–1388 (1974).CrossRefGoogle Scholar
  12. 12.
    K. A. Black, V. Virayotha, and T. R. Tephly. Reduction of hepatic tetrahydrofolate and inhibition of exhalation of14CO2 formed from [dimethylamino-14C] aminopyrine in nitrous oxide-treated rats.Hepatology 4:871–876 (1984).PubMedCrossRefGoogle Scholar
  13. 13.
    K. A. Black and T. R. Tephly. Effects of nitrous oxide and methotrexate administration on hepatic methionine synthetase and dihydrafolate reductase activities, hepatic folates and formate oxidation in rats.Mot. Pharmacol. 23:724–730 (1983).Google Scholar
  14. 14.
    C. Waydhas, H. Sies, and E. L. R. Stokstad. Methionine and thyroid hormone effects on14CO2 exhalation from [dimethylamino-14C] aminopyrine in intact phenobarbital-treated rats.FEBS Lett. 103:366–369 (1979).PubMedCrossRefGoogle Scholar
  15. 15.
    H.-U. Bieri and J. Bircher. L-Methionine ordinarily does not interfere with the aminopyrine breath test: Studies in dogs and rats.Biochem. Pharmacol. 30:1421–1424 (1981).PubMedCrossRefGoogle Scholar
  16. 16.
    D. A. Schoeller, J. F. Schneider, N. W. Solomon, J. B. Watkins, and P. D. Klein. Clinical diagnosis with the stable isotope13C in CO2 breath tests: Methodology and fundamental considerations.J. Lab. Clin. Med. 90:412–421 (1977).PubMedGoogle Scholar
  17. 17.
    D. A. Schoeller, A. L. Blake, P. S. Monroe, P. S. Krager, and J. F. Schneider. Comparison of different methods of expressing results of the aminopyrine breath test.Hepatology 2:455–462 (1982).PubMedCrossRefGoogle Scholar
  18. 18.
    J. B. Saunders, K. O. Lewis, and A. Paton. Early diagnosis of alcoholic cirrhosis by the aminopyrine breath test.Gastroenterology 79:112–114 (1980).PubMedGoogle Scholar
  19. 19.
    C. W. Lo, E. A. Carter, and W. A. Walker. Breath tests: Principles, problems, and promise.Adv. Pediatr. 29:105–127 (1982).PubMedGoogle Scholar
  20. 20.
    J. B. Houston, G. F. Lockwood, and G. Taylor. Aminopyrine demethylation kinetics. Use of metabolite exhalation rates as an index of enhanced mixed-function oxidase activityin vivo.Drug Metab. Dispos. 9:449–455 (1981).PubMedGoogle Scholar
  21. 21.
    D. A. Henry, G. Sharpe, S. Chaplain, S. Cartwright, G. Kitchingman, G. D. Bell, and M. J. S. Langman. The [14C]-aminopyrine breath test. A comparison of different forms of analysis.Br. J. Clin. Pharmacol. 8:539–545 (1979).PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    G. J. Atta and G. A. Hutchinson.MLAB, 2nd ed. Laboratory of Statistical and Mathematical Methodology, Division of Computer Research and Technology, National Institutes of Health, 1983.Google Scholar
  23. 23.
    M. Shapiro.Graph Program. Laboratory of Statistical and Mathematical Methodology, Division of Computer Research and Technology, National Institutes of Health, 1984.Google Scholar
  24. 24.
    M. M. Callahan, R. S. Robertson, M. J. Arnaud, A. R. Branfman, M. F. McComish, and D. W. Yesair. Human metabolism of [1-methyl-14C] and [2-14C] caffeine after oral administration.Drug Metab. Dispos. 10:417–423 (1982).PubMedGoogle Scholar
  25. 25.
    D. R. Abernethy, D. J. Greenblatt, and R. I. Shader. Imipramine disposition in users of oral contraceptive steroids.Clin. Pharmacol. Ther. 35:792–797 (1984).PubMedCrossRefGoogle Scholar
  26. 26.
    A. Nagy and R. Johansson. Plasma levels of imipramine and desipramine in man after different routes of administration.Naunyn-Schmiedeberg's Arch. Pharmacol. 290:145–160 (1975).CrossRefGoogle Scholar
  27. 27.
    T. A. Sutfin, C. L. DeVane, and W. J. Jusko. The analysis and disposition of imipramine and its active metabolites in man.Psychopharmacology 82:310–317 (1984).PubMedCrossRefGoogle Scholar
  28. 28.
    U. Breyer-Pfaff, M. Hardner, and E.-H. Egberts. Plasma levels of parent drug and metabolites in the intravenous aminopyrine breath test.Eur. J. Clin. Pharmacol 21:521–528 (1982).PubMedCrossRefGoogle Scholar
  29. 29.
    C. S. Irving, D. A. Schoeller, K. Nakamura, A. L. Baker, and P. D. Klein. The aminopyrine breath test as a measure of liver function. A quantitative description of its metabolic basis in normal subjects.J. Lab. Clin. Med. 100:356–373 (1982).PubMedGoogle Scholar
  30. 30.
    G. W. Hepner and E. S. Vesell. Assessment of aminopyrine metabolism in man by breath analysis after oral administration of14C-aminopyrine.N. Engt J. Med. 26:1384–1388 (1974).CrossRefGoogle Scholar
  31. 31.
    S. A. Kaplan, M. L. Jack, K. Alexander, and R. E. Weinfeld. Pharmacokinetic profile of diazepam in man following single intravenous and oral and chronic oral administrations.J. Pharm. Sci. 62:1789–1796 (1973).PubMedCrossRefGoogle Scholar
  32. 32.
    H. H. Dasberg. Effects and plasma levels ofN-desmethyldiazepam after oral administration in normal volunteers.Psychopharmacologia (Berl.) 43:191–198 (1975).CrossRefGoogle Scholar
  33. 33.
    C. L. DeVane, M. Savett, and W. J. Jusko. Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers.Eur. J. Clin. Pharmacol. 19:61–64 (1981).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1986

Authors and Affiliations

  • Elizabeth A. Lane
    • 1
  • Ioanis Parashos
    • 1
  1. 1.Laboratory of Clinical Studies, DICBRNational Institute on Alcohol Abuse and AlcoholismWashington, D.C.

Personalised recommendations