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Pharmacokinetic Interactions with Rifampicin

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Summary

Rifampicin, a potent antituberculosis agent, is frequently combined with other antituberculosis drugs, or with drugs belonging to entirely different classes which may be required during a long period of antituberculous treatment, and therefore has a potential for drug interactions of practical clinical importance.

The absorption of rifampicin is markedly decreased when it is simultaneously administered with para-aminosalicylic acid granules, due to adsorption by an excipient, bentonite. Several clinical observations and investigations have indicated that rifampicin itself accelerates the metabolism of various other compounds, including oral anticoagulants, the contraceptive pill, oral hypoglycaemic agents and digitoxin.

Rifampicin seems to be a potent inducer of drug metabolism in humans and it causes a proliferation of the smooth endoplasmatic reticulum and an increase of cytochrome P450 content in the liver. It also increases its own rate of desacetylation. However, of the lest compounds hexobarbitone and tolbutamide, the metabolic clearance increased 2- to 3-fold following rifampicin treatment, whereas antipyrine clearance was unaltered. This indicates that there is a certain selectivity in the enzyme induction effect of rifampicin, although it remains unclear which compound will and which will not be affected.

Rifampicin may also possibly interfere with hepatic uptake of other compounds, but the clinical significance of this type of interaction has not been clearly demonstrated. On the other hand, oral probenecid significantly increases the serum level of rifampicin, probably due to a similar depression of hepatic uptake.

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References

  • Acocella, G. and Billing, B.H.: The effect of rifamycin SV on bile pigment excretion in rats. Gastroenterology 49: 526–530 (1965).

    PubMed  CAS  Google Scholar 

  • Acocella, G.; Bonollo, L.; Garimoldi, M.; Mainardi, M.; Tenconi, L.T. and Nicolis, F.B.: Kinetics of rifampicin and isoniacid administered alone and in combination to normal subjects and patients with liver disease. Gut 13: 47–53 (1972a).

    Article  PubMed  CAS  Google Scholar 

  • Acocella, G., Bonollo, L.; Mainardi, M.; Margarolli, P. and Nicolis, F.B.: Kinetic studies on rifampicin. III. Effect of phenobarbital on the half-life of the antibiotic. Tijdschrift voor Gastro-Enterologie 17: 151–158 (1974).

    PubMed  CAS  Google Scholar 

  • Acocella, G.; Nicolis, F.B. and Tenconi, L.T.: The effect of an intravenous infusion of rifamycin SV on the excretion of bilirubin, bromsulphalein and indocynine green in man. Gastroenterology 49: 521–525 (1965).

    PubMed  CAS  Google Scholar 

  • Alien, B.W.; Ellard, G.A.; Mitchison, D.A.; Hatfield, A.R.W.; Kenwright, S. and Levi, A.J.: Probenecid and serum rifampicin. Lancet 2: 1309 (1975).

    Article  Google Scholar 

  • Beran, G.: Der Einfluss der Rifampicintherapie auf die orale Antikoagulation mit Acenocumarol. Praxis der Pneumologie 26: 350–353 (1972).

    CAS  Google Scholar 

  • Boekhout-Mussert, M.J.; Bieger, R.; Van Brummelen, P. and Lemkes, H.H.P.J.: Inhibition by rifampicin of the anticoagulant effect of phenprocoumon. Journal of the American Medical Association 229: 1903–1904 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Bolt, H.M.; Kappus, H. and Bolt, M.: Effect of rifampicin treatment on the metabolism of oestradiol and 17α-ethinyloestradiol by human liver microsomes. European Journal of Clinical Pharmacology 8: 301–307 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Boman, G.: Serum concentration and half-life of rifampicin after simultaneous oral administration on aminosalicylic acid or isoniacid. European Journal of Clinical Pharmacology 7: 217–225 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Boman, G.; Hanngren, A.; Malborg, A.S.; Borga, O. and Sjöqvist, F.: Drug interaction: decreased serum concentrations of rifampicin when given with PAS. Lancet 1: 800 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Boman, G.; Lundgren, P. and Stjernström, G.: Mechanism of the inhibitory effect of PAS granules on the absorption of rifampicin: adsorption of rifampicin by an excipient, bentonite. European Journal of Clinical Pharmacology 8: 293–299 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Breimer, D.D.; Zilly, W. and Richter, E.: The influence of rifampicin on drug metabolism in humans: discrepancy between hexobarbital and antipyrine. Clinical Pharmacology and Therapeutics. In Press (1976).

  • Bush, M.T. and Weller, W.L.: Metabolic fate of hexobarbital (HB). Drug Metabolism Reviews 1: 249–290 (1972).

    Article  CAS  Google Scholar 

  • Conney, A.H.: Pharmacological implications of microsomal enzyme induction. Pharmacological Reviews 19: 317–366 (1967).

    PubMed  CAS  Google Scholar 

  • Curci, G.; Ninni, A. and Jodice, F.: Quelques considerations sur la pharmacocinetique de la rifampicine. Acta Tuberculosea et Pneumologica Belgia 60: 276–287 (1969).

    CAS  Google Scholar 

  • Curci, G.; Ninni, A. and Fabbrocini, V.: Ricerche sul legame farmacoproteico e sul metabolismo della Rifampicina. Riforma Medica 8: 1–18 (1970).

    Google Scholar 

  • De Rautlin de la Roy, Y.; Beauchant, G.; Brenil, K. and Patte, F.: Diminution du taux serique de rifampiane per le phenobarbital. Presse Medicale 79: 350 (1971).

    CAS  Google Scholar 

  • Edwards, O.M.; Courtenoy-Evans, R.J.; Galley, J.M.; Hunter, J. and Tait, A.D.: Changes in Cortisol metabolism following rifampicin therapy. Lancet 2: 549–551 (1974).

    Article  Google Scholar 

  • Fallon, R.J.; Lees, A.W.; Allan, G.W.; Smith, J. and Tyrrell, W.F.: Probenecid and rifampicin serum levels. Lancet 2: 792–794 (1975).

    Article  PubMed  CAS  Google Scholar 

  • Furesz, S.; Scotti, R.; Pallanza, R. and Mapelli, E.: Rifampicin: a new Rifamycin. III: Absorption, distribution and elimination in man. Arzneimittelforschung 17: 534–537 (1967).

    PubMed  CAS  Google Scholar 

  • Gelber, R.H.; Gooi, H.C. and Rees, R.J.W.: The effect of rifampicin on dapsone metabolism. Proceedings of Western Pharmacological Society 18: 330–334 (1975).

    CAS  Google Scholar 

  • Grassi, G.G. and Grassi, C.: Ethanol- antibiotic interactions at hepatic level. International Journal of Clinical Pharmacology 11: 216–225 (1975).

    CAS  Google Scholar 

  • Grassi, G.G.; de Santis, G. and Giura, R.: Attivita dei microsomi polmonari sulla metabolizzazione di farmaci antitubercolari. Giornale Italiano Di Chemotherapia 19: 72–78 (1972).

    Google Scholar 

  • Greenberger, N.J. and Thomas, F.B.: Biliary excretion of 3H-digitoxin: modification by bile salts and phenobarbital. Journal of Laboratory and Clinical Medicine 81: 241–251 (1973).

    PubMed  CAS  Google Scholar 

  • Hakim, J.; Fledmann, G.; Boivin, P.; Troube, H.; Boucherot, J.; Penaud, J., Guibout, P. and Kreis, B.: Comparative study of hepatic bilirubin and paranitrophenol glucuronyl transferase activities. III. Effect of rifampicin alone or associated with streptomycin and isoniazid in man. Pathologie-Biologie 21: 255–263 (1973).

    PubMed  CAS  Google Scholar 

  • Held, H.; Eisert, R. and von Oldershausen, H.F.: Pharmakokinetik von Glymidine (Glycodiazin) und Tolbutamid bei akuten und chronischen Leberschäden. Arnzeimttelforchung 23: 1801–1807 (1973).

    CAS  Google Scholar 

  • Held, H.; Schoene, B.; Laar, H.J. and Fleischmann, R.: Die Aktivität der Benzepyrenhydroxylase im Leberpunktat des Menschen in vitro und ihre Beziehung zur Eliminationsgeschwindigkeit von Glycodiazin in vivo. Verhandlungen der Deutschen Gesellschaft für Innere Medizin 80: 501–503 (1974).

    PubMed  CAS  Google Scholar 

  • Hempel, E. and Klinger, W.; Drug stimulated biotransformation of hormonal steroid contraceptives: Clinical implications. Drugs 12: 442–448 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Hirsch, A.; Tillement, J.P. and Chretien, J.: Unfavourable effect of rifampicin on oral contraceptives. Report of three undesired pregnancies observed in two patients. Revues Francaise des Maladies Respiratoires 3: 174 (1975).

    Google Scholar 

  • Hunter, J.; Maxwell, J.D.; Steward, D.A.; Carella, M. and Williams, R.: Urinary D-glucaric acid excretion and total liver content of cytochrome P-450 in guinea pigs: relationship during enzyme induction and following inhibition of protein synthesis. Biochemical Pharmacology 22: 743–747 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Ikeda, M.; Conney, A.H. and Burns, J.J.: Stimulatory effect of phenobarbital and insecticides on warfarin metabolism in the rat. Journal of Pharmacology and Experimental Therapeutics 162: 338–343 (1968).

    PubMed  CAS  Google Scholar 

  • Jezequel, A.M.; Orlandi, F. and Tenconi, L.T.: Changes of the smooth endoplasmic reticulum induced by rifampicin in human and guinea-pig hepatocytes. Gut 12: 984–987 (1971).

    Article  PubMed  CAS  Google Scholar 

  • Keberle, H.; Schmid, K. and Meyer-Brunot, H.G.: The metabolic fate of Rimactane in the animal and in man; in A Symposium on Rimactane p.20–27 (Ciba, Basel 1968).

    Google Scholar 

  • Kenwright, S. and Levi, A.J.: Impairment of hepatic uptake of rifampicin antibiotics by probenecid and its therapeutic implications. Lancet 2: 1401–1405 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Kenwright, S. and Levi, A.J.: Sites of competition in the selective hepatic uptake of rifamycin-SV, flavaspidic acid, bilirubin and bromsulphthalein. Gut 15: 220–226 (1974).

    Article  PubMed  CAS  Google Scholar 

  • Kreek, M.J.; Garfield, J.W.; Gutjahr, C.L. and Giusti, L.M.: Rifampin-induced methadone withdrawal. New England Journal of Medicine 294: 1104–1106 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Kropp, R.: Rifampicin and Ovulationshemmer. Praxis der Pneumologie 28: 270 (1974).

    CAS  Google Scholar 

  • Lu, A.Y.H.; Levin, W.; Ryan, D.; West, S.B.; Thomas, P.; Kowalek, J.; Kuntzmann, R. and Conney, A.H.: Induction of different types of cytochrome P-450 in liver microsomes by drugs and carcinogens; in Anticonvulsant Drugs and Enzyme Induction, pp. 169–183 (Associated Scientific Publishers, Amsterdam 1976).

    Google Scholar 

  • Maggi, N.; Furesz, S.; Pallanza, R. and Pelizza, G.: Rifampicin desacetylation in the human organism. Arzneimittel-Forschung 19: 651–654 (1969).

    PubMed  CAS  Google Scholar 

  • Michot, F.; Burgi, M. and Buttner, J.: Rimactan (Rifamipizin) und Antikoagulantientherapie. Schweizer Medizinische Wochenschrift 100: 583–584 (1970).

    CAS  Google Scholar 

  • Mitchell, J.R. and Jollows, D.J.: Metabolic activation of drugs to toxic substances. Gastroenterology 68: 392–410 (1975).

    PubMed  CAS  Google Scholar 

  • Nitti, V.; Ninni, A.; Meola, G.; Julians, A. and Curci, G.: Comparative investigations of the enzyme-inducing activity of rifampicin and barbiturates in man. Chemotherapy 19: 206–210 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Nitti, V.; Veneri, F.D.; Ninni, A. and Meola, G.: Rifampicin blood serum levels and half-life during prolonged administration in tuberculous patients. Chemotherapy 17: 121–129 (1972).

    Article  PubMed  CAS  Google Scholar 

  • Nocke-Finck, L.; Breuer, H. and Reimers, D.; Wirkung von Rifampicin auf den Menstruationszyklus und die Ostrogenausscheidung bei Einnahme oraler Kontrazeptiva. Deutsche Medizinische Wochenschrift 98: 1521–1523 (1973).

    Article  PubMed  CAS  Google Scholar 

  • Otani, G. and Remmer, H.: Participation of microsomal NADPH-cytochrome c reductase in the metabolism of rifampicin. Naunyn-Schmiederberg’s Archivs for Pharmacology 287 (Suppl.): R76 (1975).

    Google Scholar 

  • Pessayre, D. and Mazel, P.: Induction and inhibition of hepatic drug metabolizing enzymes by rifampicin. Biochemical Pharmacology 25: 943–949 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Peters, U.; Hausamen, T.U. and Grosse-Brockhoff, F.: Enfluss von Tuberkulostatika auf die Pharmakokinetik des Digitoxins. Deutsche Medizinische Wochenschrift 99: 2381–2386 (1974).

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly, R.A.: Interactions of sodium warfarin and rifampicin. Studies in man. Annals of Internal Medicine 81: 337–340 (1974a).

    PubMed  Google Scholar 

  • O’Reilly, R.A.: Pharmacodynamics of the oral anticoagulant drugs; in Spaet (Ed) Progress in Hemostasis and Thrombosis, vol 2, p. 175–213 Grune and Stratum, New York, 1974b).

    Google Scholar 

  • Reimers, D. and Jezek, A.: Rifampicin and andere Anti-tuberkulotika bei gleichzeitiger oraler Kontrazeption. Praxis der Pneumologie 25: 255–262 (1971).

    CAS  Google Scholar 

  • Reiss, W.; Schmid, K.; Keberle, H.; Dettli, L. and Spring, P.: Pharmacokinetic studies in the field of rifamycins; in proceedings of the 6th International Congress on Chemotherapy, p.80–88 (Tokyo 1969).

    Google Scholar 

  • Schoene, B.; Fleischmann, R.A. and Remmer, H.: The cytochrome P-450 content and the activities of various microsomal enzymes in human liver. Proceedings of the European Society for the Study of Drug Toxicity 13: 249–253 (1973).

    Google Scholar 

  • Skolnick, J.L.; Szg, B.S.; Katz, D.B. and Anderson, W.H.: Rifampin, oral contraceptives, and pregnancy. Journal of the American Medical Association 236: 1382 (1976).

    Article  PubMed  CAS  Google Scholar 

  • Syvälahti, E.K.G.; Pihlajamäki, K.K. and Iisalo, E.J.: Rifampicin and drug metabolism. Lancet 2: 232–233 (1974).

    Article  PubMed  Google Scholar 

  • Thomas, R.C. and Ikeda, G.J.: The metabolic fate of tolbutamide in man and in the rat. Journal of Medicinal Chemistry 9: 507–518 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Vessel, E.S. and Page, J.G.: Genetic control of the phenobarbital-induced shortening of plasma antipyrine half-lives in man. Journal of Clinical Investigations 48: 2202–2209 (1969).

    Article  Google Scholar 

  • Vöhringer, H.F. and Rietbrock, N.: Metabolism and excretion of digitoxin in man. Clinical Pharmacology and Therapeutics 5: 796–806 (1974).

    Google Scholar 

  • Zilly, W.; Breimer, D.D. and Richter, E.: Induction of drug metabolism in man after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. European Journal of Clinical Pharmacology 9: 219–227 (1975a).

    Article  PubMed  CAS  Google Scholar 

  • Zilly, W.; Wernze, H.; Buchenau, D.; Breimer, D.D. and Richter, E.: Enfluss von Rifampicin auf die metabolische Clearance von Galaktose und Antipyrin im Vergleich zu Hexobarbital. Verhandlungen der Deutschen Gesellschaft fur Innere Medizin 81: 1677–1680 (1975b).

    PubMed  CAS  Google Scholar 

  • Zilly, W.; Breimer, D.D. and Richter, E.: Stimulation of drug metabolism in patients with liver cirrhosis and cholestasis after rifampicin treatment measured by increased hexobarbital and tolbutamide clearance. European Journal of Clinical Pharmacology. In Press (1976a).

  • Zilly, W.; Frank, W.; Richter, E. and Rietbrock, N.: unpublished results (1976b).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Würzburg, Leiden, The Netherlands

    W. Zilly, D. D. Breimer & E. Richter

  2. Department of Pharmacology, Subfaculty of Pharmacy, University of Leiden, Leiden, The Netherlands

    W. Zilly, D. D. Breimer & E. Richter

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  1. W. Zilly
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  2. D. D. Breimer
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  3. E. Richter
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Zilly, W., Breimer, D.D. & Richter, E. Pharmacokinetic Interactions with Rifampicin. Clin Pharmacokinet 2, 61–70 (1977). https://doi.org/10.2165/00003088-197702010-00005

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