, Volume 60, Issue 10, pp 709-715
Date: 13 Oct 2004

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

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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 (AUC0-24 h/BW) yielded a trend of reduction (249±98.2 h μg l−1 kg−1 versus 315±65.0 h μg l−1 kg−1, P=0.06). The AUC0-24 h/BW of desethylchloroquine was reduced by 35% (104±40.3 h μg l−1 kg−1 versus 159±66.6 h μg 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).

Conclusion

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.