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The kinetics and disposition of chloroquine (CQ) and its metabolite monodesethylchloroquine (CQM) were investigated in 5 healthy volunteers after incremental (150-300-600mg CQ base) single oral doses of CQ. The analytical method used (HPLC and fluorescence detection) is the most sensitive known method for CQ and CQM. Plasma and whole blood concentrations of CQ, CQM and a third metabolite, bidesethylchloroquine (CQMM), were determined. The kinetics of CQ was found to be unique. The best fit was obtained by a multicompartmental model. The biological half-life appeared to be between 30-60 days; the volume of distribution (Vd) was approximately 8001/kg, and the clearance approximately 11/h/kg when calculated from plasma data. The whole blood concentrations were approximately 8-10 times higher than in plasma, and consequently the Vd and whole blood clearance were approximately 10 times lower. The kinetics changed as the dose was increased. An indication of capacity-limited steps in CQ disposition was found, as the rate constants decreased even though the clearance remained the same. The intrinsic half-life of CQM was 1/4 of that of CQ, but was prolonged after the highest dose of CQ. The present knowledge of CQ kinetics could provide a basis for revision of current dosage regimens in malaria suppression and rheumatoid disease to ensure efficacious and safe therapy.

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