Skip to main content
SpringerLink
Log in

Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Objective

Rifampicin greatly reduces the plasma concentrations of many drugs. Our aim was to characterise the inducibility of cytochrome P450 (CYP) 1A2 by rifampicin, using tizanidine and caffeine as probe drugs for presystemic and systemic CYP1A2-mediated metabolism.

Methods

In a randomised, 2-phase crossover study, ten healthy volunteers were given a 5-day pretreatment with 600 mg rifampicin or placebo once daily. On day 6, a single 4-mg dose of tizanidine was administered orally. Plasma and urine concentrations of parent tizanidine and several of its metabolites (M-3, M-4, M-5, M-9, M-10) and pharmacodynamic variables were measured up to 24 h. A caffeine test was performed in both phases.

Results

Rifampicin moderately reduced the peak plasma concentration (by 51%; P=0.002) and area under the plasma concentration-time curve [AUC(0–∞)] (by 54%; P=0.009) of parent tizanidine, and had no effect on its half-life. The tizanidine/M-3 and tizanidine/M-4 AUC(0–∞) ratios were slightly (by 30%; P=0.014; and by 38%; P=0.007) decreased by rifampicin. Also, the excretion of metabolites M-3, M-4 and M-5 into urine was reduced (P<0.005), but that of M-10 was increased (P=0.008) by rifampicin. Rifampicin reduced the tizanidine/M-10 ratio (by 55%; P=0.047) but had no significant effect on the other tizanidine/metabolite ratios in urine. The caffeine/paraxanthine ratio was reduced by 23% (P=0.081) by rifampicin. The effect of rifampicin on the caffeine/paraxanthine ratio correlated significantly with the effect of rifampicin on, for example, the AUC(0–∞) of tizanidine and the tizanidine/M-3 AUC(0–∞) ratio. The pharmacodynamic effects of tizanidine were reduced by rifampicin.

Conclusions

Rifampicin moderately decreases the plasma concentrations of tizanidine. The strong inducing effects of rifampicin on other CYP enzymes, e.g. CYP3A4, may have contributed to the findings, and the inducibility of CYP1A2-mediated presystemic (tizanidine) and systemic (tizanidine, caffeine) metabolism by rifampicin is weak at the most. Compared to CYP3A4 substrate drugs, substrates of CYP1A2 are much less susceptible to drug interactions caused by enzyme inducers of the rifampicin type.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Combalbert J, Fabre I, Fabre G, Dalet I, Derancourt J, Cano JP, Maurel P (1989) Metabolism of cyclosporin A. IV. Purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug Metab Dispos 17:197–207

    PubMed  CAS  Google Scholar 

  2. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB (1992) Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small bowel enterocytes. J Clin Invest 90:1871–1878

    Article  PubMed  CAS  Google Scholar 

  3. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT (2003) Pharmacokinetic interactions with rifampicin: clinical relevance. Clin Pharmacokinet 42:819–850

    Article  PubMed  CAS  Google Scholar 

  4. Backman JT, Olkkola KT, Neuvonen PJ (1996) Rifampin drastically reduces plasma concentrations and effects of oral midazolam. Clin Pharmacol Ther 59:7–13

    Article  PubMed  CAS  Google Scholar 

  5. Villikka K, Kivistö KT, Backman JT, Olkkola KT, Neuvonen PJ (1997) Triazolam is ineffective in patients taking rifampin. Clin Pharmacol Ther 61:8–14

    Article  PubMed  CAS  Google Scholar 

  6. Lamberg TS, Kivistö KT, Neuvonen PJ (1998) Concentrations and effects of buspirone are considerably reduced by rifampicin. Br J Clin Pharmacol 45:381–385

    Article  PubMed  CAS  Google Scholar 

  7. Kyrklund C, Backman JT, Kivistö KT, Neuvonen M, Laitila J, Neuvonen PJ (2000) Rifampin greatly reduces plasma simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 68:592–597

    Article  PubMed  CAS  Google Scholar 

  8. Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, Zundler J, Kroemer HK (1999) The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest 104:147–153

    Article  PubMed  CAS  Google Scholar 

  9. Fromm MF, Kauffmann HM, Fritz P, Burk O, Kroemer HK, Warzok RW, Eichelbaum M, Siegmund W, Schrenk D (2000) The effect of rifampin treatment on intestinal expression of human MRP transporters. Am J Pathol 157:1575–1580

    PubMed  CAS  Google Scholar 

  10. Robson RA, Miners JO, Wing LM, Birkett DJ (1984) Theophylline-rifampicin interaction: non-selective induction of theophylline metabolic pathways. Br J Clin Pharmacol 18:445–448

    PubMed  CAS  Google Scholar 

  11. Straughn AB, Henderson RP, Lieberman PL, Self TH (1984) Effect of rifampin on theophylline disposition. Ther Drug Monit 6:153–156

    Article  PubMed  CAS  Google Scholar 

  12. Wietholtz H, Zysset T, Marschall HU, Generet K, Matern S (1995) The influence of rifampin treatment on caffeine clearance in healthy man. J Hepatol 22:78–81

    Article  PubMed  CAS  Google Scholar 

  13. Soto J, Sacristan JA, Alsar MJ (1996) Use of salivary caffeine tests to assess the inducer effect of a drug on hepatic metabolism. Ann Pharmacother 30:736–739

    PubMed  CAS  Google Scholar 

  14. Jokinen MJ, Olkkola KT, Ahonen J, Neuvonen PJ (2001) Effect of rifampin and tobacco smoking on the pharmacokinetics of ropivacaine. Clin Pharmacol Ther 70:344–350

    PubMed  CAS  Google Scholar 

  15. Sarkar MA, Hunt C, Guzelian PS, Karnes HT (1992) Characterization of human liver cytochromes P-450 involved in theophylline metabolism. Drug Metab Dispos 20:31–37

    PubMed  CAS  Google Scholar 

  16. Rasmussen BB, Mäenpää J, Pelkonen O, Loft S, Poulsen HE, Lykkesfeldt J, Brøsen K (1995) Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine. Br J Clin Pharmacol 39:151–159

    PubMed  CAS  Google Scholar 

  17. Tjia JF, Colbert J, Back DJ (1996) Theophylline metabolism in human liver microsomes: inhibition studies. J Pharmacol Exp Ther 276:912–917

    PubMed  CAS  Google Scholar 

  18. Shimada T, Gillam EM, Sutter TR, Strickland PT, Guengerich FP, Yamazaki H (1997) Oxidation of xenobiotics by recombinant human cytochrome P450 1B1. Drug Metab Dispos 25:617–622

    PubMed  CAS  Google Scholar 

  19. Butler MA, Iwasaki M, Guengerich FP, Kadlubar FF (1989) Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3-demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc Natl Acad Sci USA 86:7696–7700

    Article  PubMed  CAS  Google Scholar 

  20. Tassaneeyakul W, Mohamed Z, Birkett DJ, McManus ME, Veronese ME, Tukey RH, Quattrochi LC, Gonzalez FJ, Miners JO (1992) Caffeine as a probe for human cytochromes P450: validation using cDNA-expression, immunoinhibition and microsomal kinetic and inhibitor techniques. Pharmacogenetics 2:173–183

    Article  PubMed  CAS  Google Scholar 

  21. Tassaneeyakul W, Birkett DJ, McManus ME, Veronese ME, Andersson T, Tukey RH, Miners JO (1994) Caffeine metabolism by human hepatic cytochromes P450: contributions of 1A2, 2E1 and 3A isoforms. Biochem Pharmacol 47:1767–1776

    Article  PubMed  CAS  Google Scholar 

  22. Ha HR, Chen J, Krähenbühl S, Follath F (1996) Biotransformation of caffeine by cDNA-expressed human cytochromes P-450. Eur J Clin Pharmacol 49:309–315

    Article  PubMed  CAS  Google Scholar 

  23. Ekström G, Gunnarsson UB (1996) Ropivacaine, a new amide-type local anesthetic agent, is metabolized by cytochromes P450 1A and 3A in human liver microsomes. Drug Metab Dispos 24:955–961

    PubMed  Google Scholar 

  24. Arlander E, Ekström G, Alm C, Carrillo JA, Bielenstein M, Böttiger Y, Bertilsson L, Gustafsson LL (1998) Metabolism of ropivacaine in humans is mediated by CYP1A2 and to a minor extent by CYP3A4: an interaction study with fluvoxamine and ketoconazole as in vivo inhibitors. Clin Pharmacol Ther 64:484–491

    Article  PubMed  CAS  Google Scholar 

  25. Kobayashi Y, Sakai R, Ohshiro N, Ohbayashi M, Kohyama N, Yamamoto T (2005) Possible involvement of organic anion transporter 2 on the interaction of theophylline with erythromycin in the human liver. Drug Metab Dispos 33:619–622

    Article  PubMed  CAS  Google Scholar 

  26. Poland A, Glover E, Kende AS (1976) Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase. J Biol Chem 251:4936–4946

    PubMed  CAS  Google Scholar 

  27. Tirona RG, Kim RB (2005) Nuclear receptors and drug disposition gene regulation. J Pharm Sci 94:1169–1186

    Article  PubMed  CAS  Google Scholar 

  28. Fuhr U, Rost KL (1994) Simple and reliable CYP1A2 phenotyping by the paraxanthine/caffeine ratio in plasma and in saliva. Pharmacogenetics 4:109–116

    Article  PubMed  CAS  Google Scholar 

  29. Fuhr U, Rost KL, Engelhardt R, Sachs M, Liermann D, Belloc C, Beaune P, Janezic S, Grant D, Meyer UA, Staib AH (1996) Evaluation of caffeine as a test drug for CYP1A2, NAT2 and CYP2E1 phenotyping in man by in vivo versus in vitro correlations. Pharmacogenetics 6:159–176

    Article  PubMed  CAS  Google Scholar 

  30. Spigset O, Hägg S, Söderström E, Dahlqvist R (1999) The paraxanthine:caffeine ratio in serum or in saliva as a measure of CYP1A2 activity: when should the sample be obtained? Pharmacogenetics 9:409–412

    Article  PubMed  CAS  Google Scholar 

  31. Faber MS, Jetter A, Fuhr U (2005) Assessment of CYP1A2 activity in clinical practice: why, how, and when? Basic Clin Pharmacol Toxicol 97:125–134

    Article  PubMed  CAS  Google Scholar 

  32. Dollery C (1999) Caffeine. In: Dollery C (ed) Therapeutic drugs. Churchill Livingstone, Edinburgh, pp C4–C6

    Google Scholar 

  33. Koch P, Hirst DR, von Wartburg BR (1989) Biological fate of sirdalud in animals and man. Xenobiotica 19:1255–1265

    Article  PubMed  CAS  Google Scholar 

  34. Granfors MT, Backman JT, Laitila J, Neuvonen PJ (2004) Tizanidine is mainly metabolized by cytochrome p450 1A2 in vitro. Br J Clin Pharmacol 57:349–353

    Article  PubMed  CAS  Google Scholar 

  35. Granfors MT, Backman JT, Neuvonen M, Ahonen J, Neuvonen PJ (2004) Fluvoxamine drastically increases concentrations and effects of tizanidine: a potentially hazardous interaction. Clin Pharmacol Ther 75:331–341

    Article  PubMed  CAS  Google Scholar 

  36. Brøsen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S (1993) Fluvoxamine is a potent inhibitor of cytochrome P4501A2. Biochem Pharmacol 45:1211–1214

    Article  PubMed  Google Scholar 

  37. Harder S, Fuhr U, Staib AH, Wolff T (1989) Ciprofloxacin-caffeine: a drug interaction established using in vivo and in vitro investigations. Am J Med 87:89S–91S

    Article  PubMed  CAS  Google Scholar 

  38. Granfors MT, Backman JT, Neuvonen M, Neuvonen PJ (2004) Ciprofloxacin greatly increases concentrations and hypotensive effect of tizanidine by inhibiting its cytochrome P450 1A2-mediated presystemic metabolism. Clin Pharmacol Ther 76:598–606

    Article  PubMed  CAS  Google Scholar 

  39. Pickard CE, Stewart AD, Hartley R, Lucock MD (1986) A rapid HPLC method for monitoring plasma levels of caffeine and theophylline using solid phase extraction columns. Ann Clin Biochem 23:440–446

    PubMed  CAS  Google Scholar 

  40. Holland DT, Godfredsen KA, Page T, Connor JD (1998) Simple high-performance liquid chromatography method for the simultaneous determination of serum caffeine and paraxanthine following rapid sample preparation. J Chromatogr B Biomed Sci Appl 707:105–110

    Article  PubMed  CAS  Google Scholar 

  41. Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J Clin Invest 102:1016–1023

    Article  PubMed  CAS  Google Scholar 

  42. Honkakoski P, Sueyoshi T, Negishi M (2003) Drug-activated nuclear receptors CAR and PXR. Ann Med 35:172–182

    Article  PubMed  CAS  Google Scholar 

  43. Rae JM, Johnson MD, Lippman ME, Flockhart DA (2001) Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays. J Pharmacol Exp Ther 299:849–857

    PubMed  CAS  Google Scholar 

  44. Morel F, Beaune PH, Ratanasavanh D, Flinois JP, Yang CS, Guengerich FP, Guillouzo A (1990) Expression of cytochrome P-450 enzymes in cultured human hepatocytes. Eur J Biochem 191:437–444

    Article  PubMed  CAS  Google Scholar 

  45. Li AP, Reith MK, Rasmussen A, Gorski JC, Hall SD, Xu L, Kaminski DL, Cheng LK (1997) Primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytochrome P450 induction potential of xenobiotics: evaluation of rifampin, rifapentine and rifabutin. Chem Biol Interact 107:17–30

    Article  PubMed  CAS  Google Scholar 

  46. Mills JB, Rose KA, Sadagopan N, Sahi J, de Morais SM (2004) Induction of drug metabolism enzymes and MDR1 using a novel human hepatocyte cell line. J Pharmacol Exp Ther 309:303–309

    Article  PubMed  CAS  Google Scholar 

  47. Roymans D, Van Looveren C, Leone A, Parker JB, McMillian M, Johnson MD, Koganti A, Gilissen R, Silber P, Mannens G, Meuldermans W (2004) Determination of cytochrome P450 1A2 and cytochrome P450 3A4 induction in cryopreserved human hepatocytes. Biochem Pharmacol 67:427–437

    Article  PubMed  CAS  Google Scholar 

  48. Maglich JM, Stoltz CM, Goodwin B, Hawkins-Brown D, Moore JT, Kliewer SA (2002) Nuclear pregnane x receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification. Mol Pharmacol 62:638–646

    Article  PubMed  CAS  Google Scholar 

  49. Madan A, Graham RA, Carroll KM, Mudra DR, Burton LA, Krueger LA, Downey AD, Czerwinski M, Forster J, Ribadeneira MD, Gan LS, LeCluyse EL, Zech K, Robertson P, Jr., Koch P, Antonian L, Wagner G, Yu L, Parkinson A (2003) Effects of prototypical microsomal enzyme inducers on cytochrome P450 expression in cultured human hepatocytes. Drug Metab Dispos 31:421–431

    Article  PubMed  CAS  Google Scholar 

  50. Wagstaff AJ, Bryson HM (1997) Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs 53:435–452

    Article  PubMed  CAS  Google Scholar 

  51. Granfors MT, Backman JT, Laitila J, Neuvonen PJ (2005) Oral contraceptives containing ethinyl estradiol and gestodene markedly increase plasma concentrations and effects of tizanidine by inhibiting cytochrome P450 1A2. Clin Pharmacol Ther 78:400–411

    Article  PubMed  CAS  Google Scholar 

  52. Branch RA, Adedoyin A, Frye RF, Wilson JW, Romkes M (2000) In vivo modulation of CYP enzymes by quinidine and rifampin. Clin Pharmacol Ther 68:401–411

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from the Helsinki University Central Hospital Research Fund, the National Technology Agency, and the Sigrid Jusélius Foundation, Finland. None of the authors has any financial or personal relationships that could be perceived as influencing the research described. The experiments comply with the current laws of Finland, and the study protocol was approved by the Ethics Committee for Studies in Healthy Subjects and Primary Care of the Hospital District of Helsinki and Uusimaa and the Finnish National Agency for Medicines.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

    Janne T. Backman, Marika T. Granfors & Pertti J. Neuvonen

Authors
  1. Janne T. Backman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marika T. Granfors
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pertti J. Neuvonen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Janne T. Backman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Backman, J.T., Granfors, M.T. & Neuvonen, P.J. Rifampicin is only a weak inducer of CYP1A2-mediated presystemic and systemic metabolism: studies with tizanidine and caffeine. Eur J Clin Pharmacol 62, 451–461 (2006). https://doi.org/10.1007/s00228-006-0127-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-006-0127-x

Keywords

Search

Navigation