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A kinetic evaluation of14CO2 in expired air after14C-methacetin administration in rats, used for thein vivo study of the metabolism of drugs

  • D. P. Thornhill
  • C. Steffen
  • K. J. Netter
Original Papers

Summary

The pharmacokinetics of the blood level and the patterns ofl4CO2 exhalation were determined simultaneously following i.v. administration of14C-methacetin to the conscious rat. The pattern of exhalation ofl4CO2 did not parallel the biexponential decline of radioactivity in the blood and a delay of 30–40 min preceeded the maximal rate ofl4CO2 exhalation. The total radioactivity exhaled remained constant at 56±4.5% (SD) of the applied dose throughout a tenfold dose range of methacetin (0.6, 4.0 and 6.0 mg/kg i.p.), administered to groups of three rats each and measured over a period of 4 hours. The pattern of radiolabel exhalation was biexponential with the low dose, linear with the medium dose and convex with the high dose. Although the total fraction of the label expired after 4 hours remained constant, the rates of exhalation at the higher dosages exhibited saturation type kinetics. At the higher dosage, since the pattern of14CO2 exhalation did not accurately reflect the decline of methacetin seen in blood, one of the steps occuring between the demethylation process and the production of expired CO2 appears to be rate limiting.

Significant increases in the amount ofl4CO2 exhaled within 1 hour were obtained by pretreatment with phenobarbital, rifampicin and 3-methylcholanthrene. Again the proportion of radiolabel expired in 4 hours remained constant.

Acute hepatic injury produced by pretreatment with graded doses of carbon tetrachloride resulted in graded reductions in the amount of14CO2 exhaled in the first hour, although the total amount exhaled during the 4 hour collection period did not change. This resulted from a reduction in the maximal exhalation rate and a prolongation of the overall elimination process.

It is concluded that the determination of the maximal exhalation rate and of cumulative exhalation within one hour provides useful measures ofl4C-methacetin demethylation capacity. This is also true for conditions of extensive liver damage where terminal exhalation rates cannot easily be determined.

Key words

Methacetin breath test rat 

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References

  1. 1.
    Fromm H., Thomas P.J., Hofmann A.F. (1973): Sensitivity and specificity in tests of distal ileal function: Prospective comparison of bile acid and vitamin B12 absorption in ileal resection patients. Gastroenterology, 64: 1077–1090.PubMedGoogle Scholar
  2. 2.
    Kaihara S., Wagner jr. H.S. (1968): Measurement of intestinal fat absorption with carbon-14 labeled tracers. J. Lab. Clin. Med.,71, 400–411.PubMedGoogle Scholar
  3. 3.
    Hepner G.W., Vessel E.S. (1974): Assessment of aminopyrine metabolism in man by breath analysis after oral administration ofl4C-aminopyrine: Effects of phenobarbital, disulfiram and portal cirrhosis. N. Eng. J. Med.,291, 1384–1388.CrossRefGoogle Scholar
  4. 4.
    Hepner G.W., Vesell E.S. (1975): Quantitative assessment of hepatic function by breath analysis after oral administration ofl4C-aminopyrine. Ann. Int. Med.,83, 632–638.PubMedGoogle Scholar
  5. 5.
    Hepner G.W., Vessel E.S. (1976): Aminopyrine disposition: Studies on breath, saliva and urine of normal subjects and patients with liver diseases. Clin. Pharmacol. Ther.,20, 654–660.PubMedGoogle Scholar
  6. 6.
    Lauterburg B.H., Bircher J. (1976): Expiratory measurement of maximal aminopyrine demethylationin vivo. Effect of phenoarbital, partial hepatectomy, portacaval shunt and bile duct ligation in the rat. J. Pharmacol. Exp. Ther.,196, 501–509.PubMedGoogle Scholar
  7. 7.
    Schneider J.F., Schoeller D.A., Nemchausky B., Boyer J.L., Klein P. (1978): Validation of13CO2 breath analysis as a measurement of demethylation of stable isotope labeled aminopyrine in man. Clin. Chim. Acta,84, 153–162.CrossRefPubMedGoogle Scholar
  8. 8.
    Platzer R., Galeazzi R.L., Karlaganis G., Bircher J. (1978): Rate of drug metabolism in man measured byl4CO2 breath analysis. Europ. J. Clin. Pharmacol.,14, 293–299.CrossRefGoogle Scholar
  9. 9.
    Desmond P.V., Branch A., Calder I., Schenker S. (1980): Comparison of [l4C] phenacetin and amino [l4C] pyrine breath test after acute and chronic liver injury in the rat. Proc. Soc. Exp. Biol. Med.,164, 173–177.PubMedGoogle Scholar
  10. 10.
    Leferink J.G., Maes R.A.A. (1979): STRIPACT, an interactive curve fit programme for pharmacokinetic analyses. Arzneimittelforsch,29, 1894–1898.PubMedGoogle Scholar
  11. 11.
    Houston J.B., Lockwood G.F., Taylor G. (1981): Aminopyrine demethylation kinetics. Use of metabolite exhalation rates as an index of enhanced mixed-function oxidasein vivo. Drug. Metab. Dispos.,9, 449–455.PubMedGoogle Scholar
  12. 12.
    Wagner J.G. (1963): Some possible errors in the plotting and interpretation of semilogarithmic blood level and urinary excretion data. J. Pharm. Sci.,82, 1097–1101.CrossRefGoogle Scholar
  13. 13.
    Thornhill D.P., Field S.P. (1982): Distribution of lithium elimination rate in a selected population of psychiatric patients. Europ. J. Clin. Pharmacol.,21, 351–354.CrossRefGoogle Scholar
  14. 14.
    Gikalov I., Bircher J. (1977): Dose dependence of thel4C-aminopyrine breath test. Intrasubject comparison of tracer and pharmacological doses. Europ. J. Clin. Pharmacol.,12, 229–233.CrossRefGoogle Scholar
  15. 15.
    Waydhas C., Weigl K., Sies H. (1978): The disposition of formaldehyde and formate arising from drug N-demethylations dependent on cytochrome P-450 in hepatocytes and in perfused rat liver. Europ. J. Biochem.,89, 143–150.CrossRefPubMedGoogle Scholar
  16. 16.
    Raaflaub J., Dubach U.C. (1975): On the pharmacokinetic of phenacetin in man. Europ. J. Clin. Phamacol.,8, 261–265.CrossRefGoogle Scholar
  17. 17.
    Roots I., Nigam S., Gramatzki S., Heinemeyer G., Hildebrandt A.G. (1980): Hybrid information provided by the14C-aminopyrine breath test. Studies withl4C-monomethylaminoantipyrine in the guinea pig Naunyn-Schmiedeberg’s. Arch. Pharmacol.,313, 175–178.CrossRefGoogle Scholar
  18. 18.
    Gescher A., Raymont C. (1981): Studies of the metabolism of N-methyl containing anti-tumor agents. Biochem. Pharmacol.,30, 1245–1252.CrossRefPubMedGoogle Scholar
  19. 19.
    Kato R., Kamataki T. (1982): Cytochrome P-450 as a determinant of sex difference of drug metabolism in the rat. Xenobiotica,12, 787–800.CrossRefPubMedGoogle Scholar
  20. 20.
    Rhodes J.C., Houston J.B. (1983): Antipyrine metabolite kinetics in phenobarbital and β-naphthoflavone-induced rats. Drug Metab. Dispos.,11, 131–136.PubMedGoogle Scholar
  21. 21.
    Breyer-Pfaff U., Harder M., Egberts E.H. (1982): Plasma levels of parent drug and metabolites in the intravenous aminopyrine breath test. Europ. J. Clin. Phamacol.,21, 521–528.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1984

Authors and Affiliations

  • D. P. Thornhill
    • 1
  • C. Steffen
    • 2
  • K. J. Netter
    • 2
  1. 1.Department of Clinical PharmacologyUniversity of ZimbabweZimbabwe
  2. 2.Department of PharmacologyPhilipps-UniversityLahnberge, MarburgF.R.G.

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