title: Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Rengelshausen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Margit
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Yorki
authors.initials: Y
authors.lastname: Tayrouz
authors.forename: Shio Kumar
authors.initials: SK
authors.lastname: Singh
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Riedel
authors.forename: Olaf
authors.initials: O
authors.lastname: Müller
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoppe-Tichy
authors.forename: Walter E
authors.initials: WE
authors.lastname: Haefeli
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Walter-Sack
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000892:Anti-Infective Agents, Urinary / Q000097:blood / Q000494:pharmacology*; D000962:Antimalarials / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D019540:Area Under Curve; D002738:Chloroquine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology*
chemical_list: D000892:Anti-Infective Agents, Urinary; D000962:Antimalarials; D002738:Chloroquine; D008751:Methylene Blue; C007278:desethylchloroquine