Skip to main content
Log in

Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

Morphine was administered to rats by oral, intraportal, and intravenous routes in a dose of 7.6 mg · kg −1.From the serum concentration data after intraportal administration it was calculated that the first-pass elimination of morphine in the liver amounts to 72±2% (sd). The first-pass fraction eliminated after oral administration was 85±7% (sd), thus yielding a contribution by the gut mucosa of 46% to the overall first-pass elimination after an oral dose. The results were obtained with a general compartmental model which included the kinetics of enterohepatic recirculation. The oral availability was also estimated with the aid of pharmacological effect data. This availability was in good agreement with the corresponding value determined from the serum concentration data. The results suggest that morphine is subjected to enterohepatic recirculation and that the slowest phase of decline of morphine concentrations in serum might be due to this physiological process.

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

Access this article

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. B. Dahlström, J. Johansson, and L. Paalzow. Metabolism of morphine in the perfused rat liver.Acta Pharmacol. Toxicol. 39:46–52 (1976).

    Article  Google Scholar 

  2. L. K. Beecher, A. S. Keats, F. Mosteller, and L. Lasagna. The effectiveness of oral analgesics (morphine, codeine, acetylsalicylic acid) and the problem of placebo “reactors” and “non-reactors”.J. Pharmacol. Exp. Ther. 109:393–400 (1953).

    CAS  PubMed  Google Scholar 

  3. E. Del Villar, E. Sanchez, and T. R. Tephly. Morphine metabolism. II. Studies on morphine glucuronyltransferase activity in the intestinal microsomes of rats.Drug Metab. Dispos. 2:370–374 (1974).

    PubMed  Google Scholar 

  4. K. Iwamoto and C. D. Klaassen. First pass effect of morphine in rats.J. Pharmacol. Exp. Ther. 200:236–244 (1977).

    CAS  PubMed  Google Scholar 

  5. C. T. Walsh and R. R. Levine. Studies of the enterohepatic circulation of morphine in the rat.J. Pharmacol. Exp. Ther. 195:303–310 (1975).

    CAS  PubMed  Google Scholar 

  6. C. H. March and H. W. Elliott. Distribution and excretion of radioactivity after administration of morphine-N-methyl C14 to rats.Proc. Soc. Exp. Bio. (N.Y.) 86:494–497 (1954).

    Article  CAS  Google Scholar 

  7. H. E. Dobbs, J. M. Hall, and B. Steiger. Enterohepatic circulation of etorphine, a potent analgesic, in the rat.Proc. Eur. Soc. Study Drug Toxicity 11:73–79 (1970).

    Google Scholar 

  8. J. G. Wagner.Fundamentals in Clinical Pharmacokinetics, Drug Intelligence Publications, Hamilton, Ill., 1975, pp. 119–120.

    Google Scholar 

  9. B. Dahlström and L. Paalzow. Pharmacokinetics of morphine in plasma and discrete areas of the rat brain.J. Pharmacokin. Biopharm. 3:293–301 (1975).

    Article  Google Scholar 

  10. R. A. Upton. Simple and reliable method for serial sampling of blood from rats.J. Pharm. Sci. 64:112–114 (1975).

    Article  CAS  PubMed  Google Scholar 

  11. G. Paalzow and L. Paalzow. The effects of caffeine and theophylline on nociceptive stimulation in the rat.Acta Pharmacol. Toxicol. 32:22–32 (1973).

    Article  CAS  Google Scholar 

  12. G. Paalzow, L. Paalzow, and B. Stalby. Pentazocine analgesia and regional rat brain catecholamines.Eur. J. Pharmacol. 27:78–88 (1974).

    Article  CAS  PubMed  Google Scholar 

  13. M. N. Carroll and R. K. S. Lim. Observations on the neuropharmacology of morphine and morphine-like analgesia.Arch. Int. Pharmacodyn. 125:383–403 (1960).

    CAS  PubMed  Google Scholar 

  14. F. Hoffmeister and G. Kroneberg. Experimental studies in animals on the differentiation of analgesic activity. In P. Mantegazza and F. Diccinini (eds.),Methods in Drug Evaluation, North-Holland, Amsterdam, 1966, pp. 270–277.

    Google Scholar 

  15. B. Dahlström and L. Paalzow. Quantitative determination of morphine in biological samples by gas-liquid chromatography and electron capture detection.J. Pharm. Pharmacol. 27:172–176 (1975).

    Article  PubMed  Google Scholar 

  16. M. Berman, M. F. Weiss, and E. Shahn. The routine fitting of kinetic data to models: A mathematical formalism for digital computers.Biophys. J. 2:275–287 (1962).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. M. Gibaldi, R. N. Boyes, and S. Feldman. Influence of first-pass effect on availability of drugs on oral administration.J. Pharm. Sci. 60:1338–1340 (1971).

    Article  CAS  PubMed  Google Scholar 

  18. L. I. Harrison and M. Gibaldi. Influence of cholestasis on drug elimination: Pharmacokinetics.J. Pharm. Sci. 65:1346–1348 (1976).

    Article  CAS  PubMed  Google Scholar 

  19. D. P. Vaughan, D. J. H. Mallard, A. Trainor, and M. Mitchard. General pharmacokinetic equations for linear mammillary models with drug absorption into peripheral compartments.Eur. J. Clin. Pharmacol. 8:141–148 (1975).

    Article  CAS  PubMed  Google Scholar 

  20. E. L. Dobson and H. B. Jones. The behaviour of intravenous injected particulate material.Acta Med. Scand. 144:34–71, Suppl. 273 (1952).

    Google Scholar 

  21. A. S. Nies, G. R. Wilkinson, B. D. Rush, J. T. Strother, and D. G. McDevitt. Effects of alteration of hepatic microsomal enzyme activity on liver blood flow in the rat.Biochem. Pharmacol. 25:1991–1993 (1976).

    Article  CAS  PubMed  Google Scholar 

  22. S. F. Brunk and M. Delle. Morphine metabolism in man.Clin. Pharmacol. Ther. 16:51–57 (1974).

    CAS  PubMed  Google Scholar 

  23. M. Gibaldi and B. Grundhofer. Biopharmaceutic influences on the anticholinergic effects of propantheline.Clin. Pharmacol. Ther. 18:457–461 (1975).

    CAS  PubMed  Google Scholar 

  24. V. F. Smolen and R. D. Schoenwald. Drug-absorption analysis from pharmacological data. I. Method and confirmation exemplified for the mydriatic drug tropicamide.J. Pharm. Sci. 60:96–103 (1971).

    Article  CAS  PubMed  Google Scholar 

  25. V. F. Smolen, H. R. Murdoch, W. P. Stoltman, J. W. Clevenger, L. W. Combs, and E. J. Williams. Pharmacological response data for comparative bioavailability studies of chlorpromazine oral dosage forms in humans. I. Pupilometry.J. Clin. Pharmacol. 15:734–752 (1975).

    Article  CAS  PubMed  Google Scholar 

  26. J. G. Wagner. Kinetics of pharmacologic response. I. Proposed relationships between response and drug concentration in the intact animal and man.J. Theor. Biol. 20:173–201 (1968).

    Article  CAS  PubMed  Google Scholar 

  27. B. Dahlström, L. Paalzow, G. Segre, and A. T. ågren. The relation between morphine pharmacokinetics and analgesia.J. Pharmacokin. Biopharm. 6:41–55 (1978).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This work was supported in part by grants from The Swedish Academy of Pharmaceutical Sciences.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dahlström, B.E., Paalzow, L.K. Pharmacokinetic interpretation of the enterohepatic recirculation and first-pass elimination of morphine in the rat. Journal of Pharmacokinetics and Biopharmaceutics 6, 505–519 (1978). https://doi.org/10.1007/BF01062106

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01062106

Key words

Navigation