Klinische Wochenschrift

, Volume 63, Issue 23, pp 1205–1211 | Cite as

Pharmacokinetics of oral and intravenous rifampicin during chronic administration

  • U. Loos
  • E. Musch
  • J. C. Jensen
  • G. Mikus
  • H. K. Schwabe
  • M. Eichelbaum


We investigated the pharmacokinetics of rifampicin and its major metabolites, 25-desacetylrifampicin and 3-formylrifampicin, in two groups of six patients with active pulmonary tuberculosis, who received either multiple oral or intravenous rifampicin therapy in combination with intravenous isoniazid and ethambutol. Serum concentrations of rifampicin were each determined after a single oral and intravenous test dose of 600 mg rifampicin at the beginning and after 1 and 3 weeks of tuberculostatic treatment. Analysis of rifampicin and its metabolites was performed by high-pressure liquid chromatography. It was found that, due to autoinduction of its metabolizing hepatic enzymes, the systemic clearance of rifampicin increased from 5.69 to 9.03 l/h after 3 weeks of multiple dosing. The volume of distribution of the drug was constant over the period of this study. The bioavailability of the active, orally administered rifampicin decreased from 93% after the first single oral dose to 68% after 3 weeks of oral and intravenous rifampicin therapy. Relating to the increase in systemic (hepatic) clearance, a bioavailability no lower than 90% can be predicted. The reduction to 68% indicates that, in addition to an increase of hepatic metabolism, an induction of a prehepatic “first-pass” effect resulted from multiple rifampicin doses. Our study of rifampicin metabolites confirm that prehepatic metabolism was induced, since a higher metabolic ratio resulted after the oral doses than after the intravenous rifampicin test doses. A preabsorptive process can therefore be excluded as a cause of reduced bioavailability.

Key words

Rifampicin Rifampicin metabolites Multiple dose pharmacokinetics Enzyme induction 



area under the serum concentration-time curve





t 1/2



volume of distribution


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Acocella G, Bonollo L, Garimoldi M, Mainardi M, Tenconi LT, Nicolis FB (1972) Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 13:47–53Google Scholar
  2. 2.
    Acocella G, Bonollo L, Mainardi M, Margaroli P, Tenconi LT (1977) Serum and urine concentrations of rifampicin administered by intravenous infusion in man. Arzneimittelforsch 27:1221–1226Google Scholar
  3. 3.
    Acocella G, Mattiussi R, Segre G (1978) Multicompartmental analysis of serum, urine and bile concentrations of rifampicin and desacetyl-rifampicin in subjects treated for one week. Pharmacol Res Commun 10:271–288Google Scholar
  4. 4.
    Acocella G (1978) Clinical pharmacokinetics of rifampicin. Clin Pharmacokin 3:108–127Google Scholar
  5. 5.
    Binda G, Domenichini E, Gottardi A, Orlandi B, Ortelli E, Pacini B, Fowst G (1971) Rifampicin, a general review. Arzneimittelforsch 21:1907–1977Google Scholar
  6. 6.
    Boman G (1974) Serum concentration and half-life of rifampicin after simultaneous oral administration of aminosalicylic acid or isoniazid. Europ J Clin Pharmacol 7:217–225Google Scholar
  7. 7.
    Breimer DD, Zilly W, Richter E (1977) Influence of rifampicin on drug metabolism: differences between hexobarbital and antipyrine. Clin Pharmacol Ther 21:470–481Google Scholar
  8. 8.
    Furesz S, Scotti R, Pallanza R, Mapelli E (1967) Rifampicin: a new rifamycin. Arzneimittelforsch 17:534–537Google Scholar
  9. 9.
    Holdiness MR (1984) Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokin 9:511–544Google Scholar
  10. 10.
    Houin G, Beucler A, Richelet S, Brioude R, Lafaix C, Tillement JP (1983) Pharmacokinetics of rifampicin and desacetylrifampicin in tuberculous patients after different rates of infusion. Ther Drug Monit 5:67–72Google Scholar
  11. 11.
    Keberle H, Krüger-Thiemer E, Sackmann W, Schmid K, Seydel J (1967) Pharmakokinetische Untersuchungen an Rifampicin. In: Spitzy KH, Haschek H (eds) Proc 5th Int Congr Chemotherapy, Wien. Vol 4, pp 157–160Google Scholar
  12. 12.
    Keberle H, Schmid K, Meyer-Brunot HG (1968) The metabolic fate of Rimactane in the animal and in man. In: Dettli L (ed) A symposium on RimactaneR. Ciba, Basel, pp 20–27Google Scholar
  13. 13.
    Kenny MT, Strates B (1981) Metabolism and pharmacokinetics of the antibiotic rifampin. Drug Metab Rev 12:159–218Google Scholar
  14. 14.
    Kohno H, Hata B, Tsuchiya T, Kubo H (1984) Enzyme induction by rifampicin and its time-dependent pharmacokinetics. Yakugaka Zasski (=J Pharmacol Soc Japan) 14:884–888Google Scholar
  15. 15.
    Lecaillon JB, Febvre N, Metayer JP, Souppart C (1978) Quantitative assay of rifampicin and three of its metabolites in human plasma, urine and saliva by high-performance liquid chromatography. J Chromatogr 145:319–324Google Scholar
  16. 16.
    Loos U, Musch E, Mackes KG, Reetz KP, Gläser R, v. Sassen W, Labedzki L, Schwabe HK, Hengstmann J, Eichelbaum M (1983) Vergleich oraler und intravenöser Rifampicin-Gabe bei der Behandlung offener Lungentuberkulosen. Prax Klin Pneumol 37:482–484Google Scholar
  17. 17.
    Mouton RP, Mattie H, Swart K, Kreukniet J, de Wael J (1979) Blood levels of rifampicin, desacetylrifampicin and isoniazid during combined therapy. J Antimicrob Chemotherapy 5:447–454Google Scholar
  18. 18.
    Musch E, Loos U, Mackes KG, Reetz KP, Gläser R, v. Sassen W, Labedzki L, Schwabe HK, Hengstmann J, Eichelbaum M (1982) Klinische Verlaufsstudie bei intravenöser Rifampicinapplikation in the Tuberkulosetherapie. Verh Dtsch Ges Inn Med 88:638–644Google Scholar
  19. 19.
    Nakagawa H, Sunahara S (1975) Glucuronidation and desacetylation in the metabolism of rifampicin in man. 23 rd Int Tuberculosis Conf, Mexico City. Cited by Acocella (4)Google Scholar
  20. 20.
    Nakagawa, H, Umene Z, Sunahara S (1979) Increased desacetyl-rifampicin and adverse reactions. Bull Int Union Against Tuberculosis 54:171–172Google Scholar
  21. 21.
    Nitti V, Virgilio R, Patricolo MR, Iuliano A (1977) Pharmacokinetic study of intravenous rifampicin. Chemotherapy 23:1–6Google Scholar
  22. 22.
    Riess W (1968) The optimum dosage schedule for Rimactane. In: Dettli L (ed) A symposium on RimactaneR. Ciba, Basel, pp 36–42Google Scholar
  23. 23.
    Remmer H, Schoene B, Fleischmann RA (1973) Induction of the unspecific microsomal hydroxylase in the human liver. Drug Metab Disp 1:224–230Google Scholar
  24. 24.
    Rowland M (1972) Influence of route of administration on drug availability. J Pharm Sci 61:70–74Google Scholar
  25. 25.
    Sachs L (1974) Angewandte Statistik, 4th edn. Springer, Berlin Heidelberg New York, p 426Google Scholar
  26. 26.
    Siegler DI, Bryant M, Burley DM, Citron KM (1974) Effect of meals on rifampicin absorption. Lancet II, 197–198Google Scholar

Copyright information

© Springer-Verlag 1985

Authors and Affiliations

  • U. Loos
    • 1
  • E. Musch
    • 1
  • J. C. Jensen
    • 1
  • G. Mikus
    • 1
  • H. K. Schwabe
    • 1
  • M. Eichelbaum
    • 1
  1. 1.Medizinische Universitätsklinik Bonn-VenusbergGermany

Personalised recommendations