European Journal of Clinical Pharmacology

, Volume 30, Issue 4, pp 467–473 | Cite as

Influence of dose and route of administration on disposition of metronidazole and its major metabolites

  • S. Loft
  • M. Døssing
  • H. E. Poulsen
  • J. Sonne
  • K. -L. Olesen
  • K. Simonsen
  • P. B. Andreasen
Originals

Summary

The influence of dose and route of administration on the kinetics of metronidazole and its major metabolites has been investigated in 8 healthy volunteers given 0.5 and 2.0 g i.v. and p.o. Metronidazole elimination kinetics from plasma could be described by an open two-compartment model. The systemic oral bioavailability of both doses was approximately 1. The total systemic clearance of the intravenous 2.0 g dose was 9% lower than that of the 0.5 g dose (p<0.05). There were no significant dose-related differences in volume or rate of distribution. The elimination half-life was similar after the four treatments with metronidazole. The major elimination pathways, renal excretion and hepatic oxidation and glucuronidation, accounted for more than 2/3 of the total systemic clearance. Clearance both by hepatic oxidative metabolism and renal excretion was significantly lower after 2.0 than after 0.5 g i.v., whereas there was no significant difference after the oral doses. The results indicate that a high therapeutic dose of metronidazole may be eliminated at a reduced rate, but this is probably not of clinical importance. No single saturable elimination pathway was identified.

Key words

metronidazole metabolism pharmacokinetics healthy volunteers 

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References

  1. 1.
    Goldman P (1980) Drug therapy — metronidazole. N Engl J Med 303: 1212–1218Google Scholar
  2. 2.
    Urtasun RC, Rabin HR, Partington J (1983) Human pharmacokinetics and toxicity of high-dose metronidazole administered orally and intravenously. Surgery 93: 145–148Google Scholar
  3. 3.
    Jensen JC, Gugler R (1983) Single and multiple-dose metronidazole kinetics. Clin Pharmacol Ther 34: 481–487Google Scholar
  4. 4.
    Wood BA, Monro AM (1975) Pharmacokinetics of tinidazole and metronidazole in women after single large oral doses. Br J Vener Dis 48: 51–53Google Scholar
  5. 5.
    Rabin HR, Urtasun RC, Partington J, Koziol D, Sharon M, Walker K (1980) High-dose metronidazole: Pharmacokinetics and bioavailability using an i.v. preparation and application of its use as a radiosensitizer. Cancer Treat Rep 64: 1087–1095Google Scholar
  6. 6.
    Amon I, Amon K, Huller H (1978) Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages. Int J Clin Pharmacol 16: 384–386Google Scholar
  7. 7.
    Solhaug JH, Bergan T, Leinebø O, Rosseland AR, Spada L, Vaagenes F (1984) The pharmacokinetics of one single preoperative dose of metronidazole or tinidazole. Scand J Gastroenterol 19 [Suppl 91]: 89–96Google Scholar
  8. 8.
    Lau A, Emmons K, Seligsohn R (1984) Metronidazole pharmacokinetics at different doses (Abstract) Clin Pharmacol Ther 35: 254Google Scholar
  9. 9.
    Kay CM, Sankey MG, Thomas LA (1980) A rapid and sensitive specific semi-micro method involving high-pressure liquid chromatography for the assay of metronidazole in plasma, saliva, serum, urine and whole blood. Br J Clin Pharmacol 9: 528–529Google Scholar
  10. 10.
    Jensen JC, Gugler R (1983) Sensitive high-performance liquid chromatographic method for the determination of metronidazole and metabolites. J Chromatogr 277: 381–384Google Scholar
  11. 11.
    Brown DR, Manno JE (1978) ESTRIP, a BASIC computer program for obtaining initial polyexponential parameter estimates. J Pharm Sci 67: 1687–1691Google Scholar
  12. 12.
    Gibaldi M, Perrier D (1975) Drugs and the pharmaceutical sciences, vol 1: Pharmacokinetics. Marcel Dekker, New YorkGoogle Scholar
  13. 13.
    Duncan DB (1955) Multiple range and multiple F-tests. Biometrics 11: 1–42Google Scholar
  14. 14.
    Bergan T, Arnold E (1980) Pharmacokinetics of metronidazole in healthy volunteers after tablets and suppositories. Chemotherapy 26: 231–241Google Scholar
  15. 15.
    Houghton GW, Smith J, Thorne PS, Templeton R (1979) The pharmacokinetics of oral and intravenous metronidazole in man. J Antimicrob Chemother 5: 621–623Google Scholar
  16. 16.
    Houghton GW, Thorne PS, Smith J, Templeton R, Collier J (1979) Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose. Br J Clin Pharmacol 8: 337–341Google Scholar
  17. 17.
    Bergan T, Leinebø O, Blom-Hagen T, Salvesen B (1984) Pharmacokinetics and bioavailability of metronidazole after tablets, suppositories and intravenous administration. Scand J Gastroenterol 19 [Suppl 91]: 45–60Google Scholar
  18. 18.
    Scwartz DE Jeunet F (1976) Comparative pharmacokinetic studies of ornidazole and metronidazole in man. Chemotherapy 22: 19–29Google Scholar
  19. 19.
    Houston JB (1982) Drug metabolite kinetics. Pharmacol Ther 15: 521–552Google Scholar
  20. 20.
    Scill G, Ehrsson H, Vessman J, Westerlund D (1984) Separation methods for drugs and related organic compounds. Swedish Pharmaceutical Press, StockholmGoogle Scholar
  21. 21.
    Stambaugh JE, Feo LG, Manthei RW (1968) The isolation and identification of the urinary metabolites of metronidazole in man. J Pharmacol Exp Ther 161: 373–381Google Scholar

Copyright information

© Springer-Verlag 1986

Authors and Affiliations

  • S. Loft
    • 1
    • 2
    • 3
  • M. Døssing
    • 1
    • 2
  • H. E. Poulsen
    • 1
    • 2
  • J. Sonne
    • 1
    • 2
  • K. -L. Olesen
    • 1
    • 2
  • K. Simonsen
    • 1
    • 2
  • P. B. Andreasen
    • 1
    • 2
  1. 1.Medical Department FGentofte University HospitalDenmark
  2. 2.Medical Department ARigshospitaletCopenhagenDenmark
  3. 3.Department of PharmacologyUniversity of CopenhagenCopenhagen ØDenmark

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