Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

• Published in: European journal of clinical pharmacology Vol. 60; no. 10; pp. 709 - 715
• Main Authors: Rengelshausen, Jens, Burhenne, J rgen, Fr hlich, Margit, Tayrouz, Yorki, Singh, Shio Kumar, Riedel, Klaus-Dieter, M ller, Olaf, Hoppe-Tichy, Torsten, Haefeli, Walter E., Mikus, Gerd, Walter-Sack, Ingeborg
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.12.2004; Berlin Springer Nature B.V
• Subjects: Administration, Oral; Adult; Anti-Infective Agents, Urinary - blood; Anti-Infective Agents, Urinary - pharmacology; Antimalarials - blood; Antimalarials - pharmacokinetics; Antimalarials - urine; Area Under Curve; Biological and medical sciences; Chloroquine - analogs & derivatives; Chloroquine - blood; Chloroquine - pharmacokinetics; Chloroquine - urine; Drug Interactions; Female; Half-Life; Humans; Malaria, Falciparum - drug therapy; Male; Medical sciences; Methylene Blue - pharmacology; Pharmacology. Drug treatments; Plasmodium falciparum; Infection; Human; Antimalarial; Protozoal disease; Malaria; Chloroquine; Interaction; Parasiticide; Parasitosis; Antirheumatic agent; Pharmacokinetics; Methylene blue
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-004-0818-0

The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine. In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose. During methylene blue exposure, the area under the chloroquine whole blood concentration-time curve normalized to body weight (AUC(0-24 h)/BW) yielded a trend of reduction (249+/-98.2 h mug l(-1) kg(-1) versus 315+/-65.0 h mug l(-1) kg(-1), P=0.06). The AUC(0-24 h)/BW of desethylchloroquine was reduced by 35% (104+/-40.3 h mug l(-1) kg(-1) versus 159+/-66.6 h mug l(-1) kg(-1), P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25+/-0.49 versus 1.95+/-0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P>0.1). Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.