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Eur J Clin Pharmacol (2009) 65:179189 DOI 10.1007/s00228-008-0563-x
PHARMACOKINETICS AND DISPOSITION
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 Mikus
Received: 10 July 2008 /Accepted: 27 August 2008 / Published online: 23 September 2008 # Springer-Verlag 2008
AbstractPurpose 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
I. Walter-Sack : J. Rengelshausen : H. Oberwittler : J. Burhenne :
G. Mikus (*)
Department of Internal Medicine VI,Clinical Pharmacology and Pharmacoepidemiology, University Hospital,Im Neuenheimer Feld 410,69120 Heidelberg, Germanye-mail: [email protected]
O. Mueller : P. MeissnerDepartment of Tropical Hygiene and Public Health, Ruprecht-Karls-University,Heidelberg, Germany
Present address:J. Rengelshausen Arensgasse 4a,52078 Aachen, Germany
Present address:H. Oberwittler34 Boulevard de Grenelle, Paris, France
Present address:P. MeissnerDepartment of Paediatrics,Department of Tropical Hygiene and Public Health, AIC Kijabe Hospital of Eldoret University, Eldoret, Kenya
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 concentrationtime curve (AUC0 1) was 7,6393,384 ng/
mL*h and 51,17117,147 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 72.323.9%. Co-administration with CQ significantly increased MB plasma concentrations (p0.016); 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.
Keywords Bioavailability. Chloroquine . Kinetics . Methylene blue
Introduction
Methylene blue (MB, methylthioninium chloride) has recently been reinvestigated for various aspects of its antimalarial activity, such as its selective inhibition of glutathione reductase of Plasmodium falciparum [2, 27], and MB-based combination therapy is currently under development for the treatment of uncomplicated malaria in Sub-Saharan Africa [1719,...