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High absolute bioavailability of methylene blue given as an aqueous oral formulation

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

Abstract

Purpose

Methylene blue (MB) has recently been reevaluated for malaria treatment. With the aim of excluding treatment failures due to low bioavailability, we have investigated the absolute bioavailability of MB given as an aqueous oral formulation and its interaction with chloroquine (CQ).

Methods

A phase I study in 16 healthy individuals was performed as a monocenter prospective open randomized intra-individual cross-over comparison of MB single doses [50 mg intravenous (i.v.), 500 mg orally, separated by a 1-week wash-out]. After a second week, the group was split for a randomized parallel group comparison of CQ 750 mg administered orally alone or combined with 500 mg MB orally.

Results

Mean MB plasma area under the substrate concentration–time curve (\({\text{AUC}}_{0 - \infty } \)) was 7,639 ± 3,384 ng/mL*h and 51,171 ± 17,147 ng/mL*h after i.v. and oral administration, respectively (dosage 1:10), and 76,897 ± 46,037 ng/mL*h after MB combined with CQ. The absolute bioavailability was 72.3 ± 23.9%. Co-administration with CQ significantly increased MB plasma concentrations (p ≤ 0.016); CQ kinetics remained unaffected.

Conclusion

The absolute bioavailability of MB is high. Co-administration of MB and CQ increases plasma, but not whole blood MB concentrations.

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References

  1. Aeschlimann C, Kuepfer A, Schefer H, Cerny T (1998) Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy. Drug Metab Dispos 26:883–890

    PubMed  CAS  Google Scholar 

  2. Akoachere M, Buchholz K, Fischer E, Burhenne J, Haefeli WE, Schirmer RH, Becker K (2005) In vitro assessment of methylene blue on chloroquine-sensitive and -resistant Plasmodium falciparum strains reveals synergistic action with artemisinins. Antimicrob Agents Chemother 49:4592–4597

    Article  PubMed  CAS  Google Scholar 

  3. Burhenne J, Riedel K-D, Rengelshausen J, Meissner P, Mueller O, Mikus G, Haefeli WE, Walter-Sack I (2008) Quantification of cationic anti-malaria agent methylene blue in different human biological matrices using cation exchange chromatography coupled to tandem mass spectrometry. J Chromatogr B 863:273–282

    Article  CAS  Google Scholar 

  4. DiSanto AR, Wagner JG (1972) Pharmacokinetics of highly ionized drugs II: methylene blue—absorption, metabolism, and excretion in man and dog after oral administration. J Pharm Sci 61:1086–1090

    Article  PubMed  CAS  Google Scholar 

  5. Donati A, Conti G, Loggi S, Muench C, Coltrinari R, Pelaia P, Pietropaoli P, Preiser J-C (2002) Does methylene blue administration to septic shock patients affect vascular permeability and blood volume. Crit Care Med 30:2271–2277

    Article  PubMed  CAS  Google Scholar 

  6. Ducharme J, Farinotti R (1996) Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 31:257–274

    Article  PubMed  CAS  Google Scholar 

  7. Ehrlich P (1913) Chemotherapeutics: scientific principles, methods, and results. Lancet 182:445–451

    Article  Google Scholar 

  8. European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (2006) Reflection paper: Formulations of choice for the pediatric population. Available at: http://www.emea.europa.eu/pdfs/human/paediatrics/19481005en.pdf. Accessed 8 July 2008

  9. Evora PR, Simon MR (2007) Role of nitric oxide production in anaphylaxis and its relevance for the treatment of anaphylactic hypotension with methylene blue. Ann Allergy Asthma Immunology 99:306–313

    Article  CAS  Google Scholar 

  10. Ferreira C (1893) Sur l`emploi du bleu de méthylène dans la malaria infantile. Rev Ther Med Chir 488–525

  11. Frisk-Holmberg M, Bergqvist Y, Termond E, Domeij-Nyberg B (1984) The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects. Eur J Clin Pharmacol 26:521–530

    Article  PubMed  CAS  Google Scholar 

  12. Gustafsson LL, Walker O, Alván G, Beermann B, Estevez F, Gleisner L, Lindstroem B, Sjoeqvist F (1983) Disposition of chloroquine in man after single intravenous and oral doses. Br J Clin Pharmacol 15:471–479

    PubMed  CAS  Google Scholar 

  13. Gut F, Schiek W, Haefeli WE, Walter-Sack I, Burhenne J (2008) Cation exchange resins as pharmaceutical carriers for methylene blue: Binding and release. Eur J Pharm Biopharm 69:582–587

    Article  PubMed  CAS  Google Scholar 

  14. Guttmann P, Ehrlich P (1891) Ueber die Wirkung des Methylenblau bei Malaria. Berlin Klin Wochenschr 28:953–956

    Google Scholar 

  15. Khan MA, North AP, Chadwick DR (2007) Prolonged postoperative altered mental status after methylene blue infusion during parathyroidectomy: a case report and review of the literature. Ann R Coll Surg Eng 89:W9–W11

    Article  CAS  Google Scholar 

  16. Kuepfer A, Aeschlimann C, Wermuth B, Cerny T (1994) Prophylaxis and reversal of ifosfamide encephalopathy with methylene blue. Lancet 343:763–764

    Article  Google Scholar 

  17. Mandi G, Witte S, Meissner P, Coulibaly B, Mansmann U, Rengelshausen J, Schiek W, Jahn A, Sanon M, Wuest K, Walter-Sack I, Mikus G, Burhenne J, Riedel K-D, Schirmer H, Kouyaté B, Mueller O (2005) Safety of the combination of chloroquine and methylene blue in healthy adult men with G6PD deficiency from rural Burkina Faso. Trop Med Int Health 10:32–38

    Article  PubMed  CAS  Google Scholar 

  18. Meissner P, Mandi G, Witte S, Coulibaly B, Mansmann U, Rengelshausen J, Schiek W, Jahn A, Sanon M, Tapsoba T, Walter-Sack I, Mikus G, Burhenne J, Riedel K-D, Schirmer H, Kouyaté B, Mueller O (2005) Safety of the combination of chloroquine and methylene blue in the treatment of uncomplicated falciparum malaria in young children of Burkina Faso. Malaria J 4:45

    Article  CAS  Google Scholar 

  19. Meissner PE, Mandi G, Coulibaly B, Witte S, Tapsoba T, Mansmann U, Rengelshausen J, Schiek W, Jahn A, Walter-Sack I, Mikus G, Burhenne J, Riedel K-D, Schirmer RH, Kouyate B, Mueller O (2006) Methylene blue for malaria in Africa: results from a dose-finding study in combination with chloroquine. Malaria J 5:84

    Article  CAS  Google Scholar 

  20. Minzi OM, Rais M, Svensson JO, Gustafsson LL, Ericsson O (2003) High-performance chromatographic method for determination of amodiaquine, chloroquine and their monodesethyl metabolites in biological samples. J Chromatogr B Analyt Technol Biomed Life Sci 783:473–480

    Article  PubMed  CAS  Google Scholar 

  21. Neto AMO, Duarte NM, Vicente WVA, Viaro F, Evora PRB (2003) Methylene blue: an effective treatment for contrast medium-induced anaphylaxis. Med Sci Monit 9:CS102–CS106

    Google Scholar 

  22. Noedl H, Chanthap L, Se Y, Socheat D, Peou S, Schaechter K, Srivichai S, Teja-Isavadharm P, Smith B, Jongsakul K, Surasri S, Fukuda M (2007) Artemisinin resistance in Cambodia. Oral presentation, 5th Eur Congress Trop Med Int Health. Amsterdam

  23. Pelgrims J, De Vos F, Van den Brande J, Schrijvers D, Prové A, Vermorken JB (2000) Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and review of the literature. Br J Cancer 82:291–294

    Article  PubMed  CAS  Google Scholar 

  24. Peter C, Hongwan D, Kuepfer A, Lauterburg BH (2000) Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 56:247–250

    Article  PubMed  CAS  Google Scholar 

  25. Politis C, Kavallierou L, Hantziara S, Katsea P, Triantaphylou V, Richardson C, Tsoutsos D, Anagnostopoulos N, Gorgolidis G, Ziroyannis P (2007) Quality and safety of fresh-frozen plasma inactivated and leuco-reduced with the Theraflex methylene blue system including the Blueflex filter: 5 years’ experience. Vox Sang 92:319–326

    PubMed  CAS  Google Scholar 

  26. Rengelshausen J, Burhenne J, Froehlich M, Tayrouz Y, Singh SK, Riedel K-D, Mueller O, Hoppe-Tichy T, Haefeli WE, Mikus G, Walter-Sack I (2004) Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria. Eur J Clin Pharmacol 60:709–715

    Article  PubMed  CAS  Google Scholar 

  27. Schirmer RH, Coulibaly B, Stich A, Scheiwein M, Merkle H, Eubel J, Becker K, Becher H, Mueller O, Zich T, Schiek W, Kouyaté B (2003) Methylene blue as an antimalarial agent. Redox Rep 8:272–275

    Article  PubMed  CAS  Google Scholar 

  28. Simonsen AC, Sørensen H (1999) Clinical tolerance of methylene blue virus-inactivated plasma. Vox Sang 77:210–217

    Article  PubMed  CAS  Google Scholar 

  29. Stevens S, Werner L, Mamalis N (2007) Corneal edema and permanent blue discoloration of a silicone intraocular lens by methylene blue. Ophthalmic Surg Lasers Imaging 38:136–141

    PubMed  Google Scholar 

  30. Williamson LM, Cardigan R, Prowse CV (2003) Methylene blue-treated fresh-frozen plasma: what is its contribution to blood safety. Transfusion 43:1322–1329

    Article  PubMed  CAS  Google Scholar 

  31. Zoungrana A, Coulibaly B, Sié A, Walter-Sack I, Mockenhaupt FP, Kouyaté B, Schirmer RH, Klose C, Mansmann U, Meissner P, Mueller O (2008) Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso. Available at: http://www.plosone.org/3:e1630

  32. Zulian GB, Tullen E, Maton B (1995) Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med 332:1239–1240

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The study was funded by an award from DSM Fine Chemicals Austria, Linz, Austria and by the Deutsche Forschungsgemeinschaft (SFB 544 “Control of Tropical Infectious Diseases” at the Ruprecht-Karls-University Heidelberg). We thank Mrs. Monika Maurer and Mrs. Brigitte Tayrouz for their excellent technical assistance.

Financial disclosure

None of the authors has financial or other relationships that are relevant to the study.

Author information

Author notes

  1. Jens Rengelshausen

    Present address: , Arensgasse 4a, 52078, Aachen, Germany

  2. Heike Oberwittler

    Present address: , 34 Boulevard de Grenelle, Paris, France

  3. Peter Meissner

    Present address: Department of Paediatrics, Department of Tropical Hygiene and Public Health, AIC Kijabe Hospital of Eldoret University, Eldoret, Kenya

Authors and Affiliations

  1. Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany

    Ingeborg Walter-Sack, Jens Rengelshausen, Heike Oberwittler, Juergen Burhenne & Gerd Mikus

  2. Department of Tropical Hygiene and Public Health, Ruprecht-Karls-University, Heidelberg, Germany

    Olaf Mueller & Peter Meissner

Authors
  1. Ingeborg Walter-Sack
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  2. Jens Rengelshausen
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  3. Heike Oberwittler
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  4. Juergen Burhenne
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  5. Olaf Mueller
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  6. Peter Meissner
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  7. Gerd Mikus
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Corresponding author

Correspondence to Gerd Mikus.

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Walter-Sack, I., Rengelshausen, J., Oberwittler, H. et al. High absolute bioavailability of methylene blue given as an aqueous oral formulation. Eur J Clin Pharmacol 65, 179–189 (2009). https://doi.org/10.1007/s00228-008-0563-x

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  • DOI: https://doi.org/10.1007/s00228-008-0563-x

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