On the pharmacokinetics of domperidone in animals and man IV. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration

  • J. Heykants
  • R. Hendriks
  • W. Meuldermans
  • M. Michiels
  • H. Scheygrond
  • H. Reyntjens
Original Papers

Summary

The pharmacokinetics and bioavailability of domperidone, a novel gastrokinetic, were studied in healthy male subjects by comparing plasma concentrations and urinary excretion following intravenous, intramuscular, oral and rectal administration. Two oral dosage forms were studied: 10-mg tablets and a 10-mg/ml oral solution. The influence of a meal on the oral bioavailability and the dose-proportionality were also investigated.

Plasma levels of intravenous domperidone could be described by a three-compartment model with a rapid distribution of 40% of the dose to as «shallow» peripheral compartment. The final elimination half-life was 7.5 hours. Peak plasma levels were reached within 30 minutes following intramuscular and oral administration and at 1–4 hours following rectal administration. Since domperidone showed an extensive first-pass elimination, AUC-values -a measure for the bioavailability- were consider-ably lower after oral than after parenteral administration. Equal oral and rectal doses gave a similar bioavailability. AUC-values increased proportionally with the dose over a 10–60 mg range. Cumulative urinary excretion of unchanged domperidone was proportional to corresponding AUC-values.

The bioavailability was discussed in the light of the therapeutic results.

Key words

domperidone gastrokinetic pharmacokinetics bioavailability man 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Niemegeers C.J.E., Schellekens K.H.L. and Janssen P.A.J. (1980): The antiemetic effects of domperidone, a novel potent gastrokinetic. Archs. int Pharmacodyn.,244, 130–140.Google Scholar
  2. 2.
    Laduron P.M. and Leysen J.E. (1979): Domperidone, a specificin vitro dopamine antagonist, devoid ofin vivo central dopaminergic activity. Biochem. Pharmac.,28, 2161–2165.CrossRefGoogle Scholar
  3. 3.
    Baudry M., Martres M.P. and Schartz J.C. (1979):3H-Domperidone: a selective ligand for dopamine receptors. Naunyn-Schmiedebergs Arch. Pharmac.,308, 231–237.CrossRefGoogle Scholar
  4. 4.
    Heykants J., Knaeps A., Meuldermans W. and Michiels M. (1981): On the pharmacokinetics of domperidone in animals and man. I. Plasma levels of domperidone in rats and dogs. Age-related absorption and passage through the blood-brain barrier in rats. Europ. J. Drug Metab. Pharmacokin. (this issue).Google Scholar
  5. 5.
    Michiels M., Hendriks R. and Heykants J. (1981): On the pharmacokinetics of domperidone in animals and man. II. Tissue distribution, placental and milk transfer of domperidone in the Wistar rat. Europ. J. Drug Metab. Pharmacokin. (this issue).Google Scholar
  6. 6.
    Van Nueten J.M., Ennis C., Helsen L., Laduron P.M. and Janssen P.A.J. (1978): Inhibition of dopamine receptors in the stomach: an explanation of the gastrokinetic properties of domperidone. Life Sci.,23, 453–458.CrossRefPubMedGoogle Scholar
  7. 7.
    Van Nueten J.M. and Janssen P.A.J. (1979): Effect of domperidone on gastric relaxation caused by dopamine, secretin, 5-hydroxytryptamine, substance P and adenosine triphosphate, 7th Int. Symposium on Gastrointestinal Motility, Iowa City.Google Scholar
  8. 8.
    Van Nueten J.M. (1980): Is dopamine an inhibitory modulator of gastric motility? TIPS, 233–235.Google Scholar
  9. 9.
    Reyntjens A.J., Niemegeers C.J.E., Van Nueten J.M., Laduron P., Heykants J., Schellekens K.H.L., Marsboom R., Jagenau A., Broekaert A. and Janssen P.A.J. (1978): Domperidone, a novel and safe gastrokinetic anti-nauseant for the treatment of dyspepsia and vomiting. A survey of pharmacological and clinical results. Arzneimittel-Forsch.,28, 1194–1196.Google Scholar
  10. 10.
    Broekaert A. (1979): Effect of domperidone on gastric emptying and secretion. Post-grad. med. J.,55, (Suppl. 1), 11–14.Google Scholar
  11. 11.
    Platteborse R. (1979): The effect of domperidone on pyloric activity in dog and in man. Post-grad. med. J.,55, (Suppl. 1), 15–18.Google Scholar
  12. 12.
    Weihrauch T.R., Förster C.F. and Krieglstein J. (1979): Evaluation of the effect of domperidone on human oesophageal and gastroduodenal motility by intraluminal manometry. Post-grad. med. J.,55, (Suppl. 1), 7–10.Google Scholar
  13. 13.
    Reyntjens A. (1979): Domperidone as an antiemetic; summary of research reports. Post-grad. med. J.,55, (Suppl. 1), 50–54.Google Scholar
  14. 14.
    Haarmann K., Lebkuchner F., Widmann A., Kief W. and Esslinger M. (1979): A double-blind study of domperidone it the symptomatic treatment of chronic postprandial upper gastrointestinal distress. Post-grad. med. J.,55, (Suppl. 1), 24–27.Google Scholar
  15. 15.
    Englert W. and Schlich D. (1979): A double-blind crossover trial of domperidone in chronic postprandial dyspepsia. Post-grad. med. J.,55, (Suppl. 1), 28–29.Google Scholar
  16. 16.
    Bekhti A. and Rutgeerts L. (1979): Domperidone in the treatment of functional dyspepsia in patients with delayed gastric emptying. Post-grad. med. J.,55, (Suppl. 1), 30–32.Google Scholar
  17. 17.
    Van Outryve M., Lauwers W. and Verbeke S. (1979): Domperidone for the symptomatic treatment of chronic post-prandial nausea and vomiting. Post-grad. med. J.,55, (Suppl. 1), 33–35.Google Scholar
  18. 18.
    Van Eygen M., Dhondt F., Heck E., Ameryckx L. and Van Ravensteyn H. (1979): A double-blind comparison of domperidone and metoclopramide suppositories in the treatment of nausea and vomiting in children. Post-grad. med. J.,55, (Suppl. 1), 36–39.Google Scholar
  19. 19.
    Clara R., Van Hollebeke J. and Heck E. (1979): A multicentre pilot study of parenteral and rectal administration of domperidone in the treatment of severe vomiting in children. Post-grad. med. J.,55, (Suppl. 1), 43–44.Google Scholar
  20. 20.
    Boulanger M., Dubois A. and Lecron L. (1979): Domperidone in the prevention of post-operative nausea and vomiting. Post-grad. med. J.,55, (Suppl. 1), 45–47.Google Scholar
  21. 21.
    Meuldermans W., Hurkmans R., Swijsen E., Hendrickx J., Michiels M., Lauwers W. and Heykants J. (1981): On the pharmacokinetics of domperidone in animals and man. III. Comparative study on the excretion and metabolism of domperidone in rats, dogs and man. Europ. J. Drug. Metab. Pharmacokin. (this issue).Google Scholar
  22. 22.
    Michiels M., Hendriks R. and Heykants J. (1980): A sensitive and specific radioimmunoassay for domperidone. Manuscript in preparation.Google Scholar
  23. 23.
    Meuldermans W.E.G. and Heykants J.J.P. (1976): The plasma protein binding and distribution of etomidate in dog, rat and human blood. Archs. int. Pharmacodyn.,221, 150–162.Google Scholar
  24. 24.
    Ehrnebo M., Agurell A., Borëus L.O., Gordon E. and Lönroth U. (1974): Pentazocine binding to blood cells and plasma proteins. Clin. Pharmac. Ther.,16, 424–429.Google Scholar
  25. 25.
    Gibaldi M. and Perrier D. (1975): Pharmacokinetics, Marcel Dekker, Inc., New York.Google Scholar
  26. 26.
    Michiels M., Heykants J. and Reyntjens A. (1981): On the pharmacokinetics of domperidone in animals and man. V. Detailed study on the distribution of domperidone in rats and dogs. Europ. J. Drug. Metab. Pharmacokin., (this issue).Google Scholar
  27. 27.
    Rowland M. (1972): Influence of route of administration on drug availability. J. Pharm. Sci.,61, 70–74.CrossRefPubMedGoogle Scholar
  28. 28.
    28. De Boer A.G. (1980): «First-pass» eliminatie van enige «high-clearance» farmaca na rectale toediening aan de mens en de rat. Pharm. Weekblad,115, 613–620.Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • J. Heykants
    • 1
    • 2
  • R. Hendriks
    • 1
    • 2
  • W. Meuldermans
    • 1
    • 2
  • M. Michiels
    • 1
    • 2
  • H. Scheygrond
    • 1
    • 2
  • H. Reyntjens
    • 1
    • 2
  1. 1.Department of Drug Metabolism and PharmacokineticsJanssen PharmaceuticaBeerseBelgium
  2. 2.Medical DepartmentJanssen PharmaceuticaBeerseBelgium

Personalised recommendations