European Journal of Clinical Pharmacology

, Volume 65, Issue 2, pp 179–189 | Cite as

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

  • Ingeborg Walter-Sack
  • Jens Rengelshausen
  • Heike Oberwittler
  • Juergen Burhenne
  • Olaf Mueller
  • Peter Meissner
  • Gerd MikusEmail author
Pharmacokinetics and Disposition



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).


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.


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.


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


Bioavailability Chloroquine Kinetics Methylene blue 



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.


  1. 1.
    Aeschlimann C, Kuepfer A, Schefer H, Cerny T (1998) Comparative pharmacokinetics of oral and intravenous ifosfamide/mesna/methylene blue therapy. Drug Metab Dispos 26:883–890PubMedGoogle Scholar
  2. 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 49:4592–4597PubMedCrossRefGoogle Scholar
  3. 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 863:273–282CrossRefGoogle Scholar
  4. 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 61:1086–1090PubMedCrossRefGoogle Scholar
  5. 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 30:2271–2277PubMedCrossRefGoogle Scholar
  6. 6.
    Ducharme J, Farinotti R (1996) Clinical pharmacokinetics and metabolism of chloroquine. Focus on recent advancements. Clin Pharmacokinet 31:257–274PubMedCrossRefGoogle Scholar
  7. 7.
    Ehrlich P (1913) Chemotherapeutics: scientific principles, methods, and results. Lancet 182:445–451CrossRefGoogle Scholar
  8. 8.
    European Medicines Agency (EMEA) Committee for Medicinal Products for Human Use (2006) Reflection paper: Formulations of choice for the pediatric population. Available at: Accessed 8 July 2008
  9. 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 99:306–313CrossRefGoogle Scholar
  10. 10.
    Ferreira C (1893) Sur l`emploi du bleu de méthylène dans la malaria infantile. Rev Ther Med Chir 488–525Google Scholar
  11. 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 26:521–530PubMedCrossRefGoogle Scholar
  12. 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 15:471–479PubMedGoogle Scholar
  13. 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 69:582–587PubMedCrossRefGoogle Scholar
  14. 14.
    Guttmann P, Ehrlich P (1891) Ueber die Wirkung des Methylenblau bei Malaria. Berlin Klin Wochenschr 28:953–956Google Scholar
  15. 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–W11CrossRefGoogle Scholar
  16. 16.
    Kuepfer A, Aeschlimann C, Wermuth B, Cerny T (1994) Prophylaxis and reversal of ifosfamide encephalopathy with methylene blue. Lancet 343:763–764CrossRefGoogle Scholar
  17. 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 10:32–38PubMedCrossRefGoogle Scholar
  18. 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 4:45CrossRefGoogle Scholar
  19. 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 5:84CrossRefGoogle Scholar
  20. 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 783:473–480PubMedCrossRefGoogle Scholar
  21. 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–CS106Google Scholar
  22. 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. AmsterdamGoogle Scholar
  23. 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 82:291–294PubMedCrossRefGoogle Scholar
  24. 24.
    Peter C, Hongwan D, Kuepfer A, Lauterburg BH (2000) Pharmacokinetics and organ distribution of intravenous and oral methylene blue. Eur J Clin Pharmacol 56:247–250PubMedCrossRefGoogle Scholar
  25. 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 92:319–326PubMedGoogle Scholar
  26. 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 60:709–715PubMedCrossRefGoogle Scholar
  27. 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 8:272–275PubMedCrossRefGoogle Scholar
  28. 28.
    Simonsen AC, Sørensen H (1999) Clinical tolerance of methylene blue virus-inactivated plasma. Vox Sang 77:210–217PubMedCrossRefGoogle Scholar
  29. 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 38:136–141PubMedGoogle Scholar
  30. 30.
    Williamson LM, Cardigan R, Prowse CV (2003) Methylene blue-treated fresh-frozen plasma: what is its contribution to blood safety. Transfusion 43:1322–1329PubMedCrossRefGoogle Scholar
  31. 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:
  32. 32.
    Zulian GB, Tullen E, Maton B (1995) Methylene blue for ifosfamide-associated encephalopathy. N Engl J Med 332:1239–1240PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Ingeborg Walter-Sack
    • 1
  • Jens Rengelshausen
    • 1
    • 3
  • Heike Oberwittler
    • 1
    • 4
  • Juergen Burhenne
    • 1
  • Olaf Mueller
    • 2
  • Peter Meissner
    • 2
    • 5
  • Gerd Mikus
    • 1
    Email author
  1. 1.Department of Internal Medicine VI, Clinical Pharmacology and PharmacoepidemiologyUniversity HospitalHeidelbergGermany
  2. 2.Department of Tropical Hygiene and Public HealthRuprecht-Karls-UniversityHeidelbergGermany
  3. 3.AachenGermany
  4. 4.ParisFrance
  5. 5.Department of Paediatrics, Department of Tropical Hygiene and Public HealthAIC Kijabe Hospital of Eldoret UniversityEldoretKenya

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