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.

handling of chloroquine over-dosages since both Br. J. clin. Pharmac. (1983),15 Br. J. clin. Pharmac. (1983, 15 LETTERS TO THE EDITORS 503 chloroquine and its metabolites have been associated with toxicity. Therefore forced acid diuresis could be recommended to enhance both the elimination of chloroquine and its more water soluble metabolites.

1. Fibre composition in the vastus lateralis muscle, and blood pressure, were determined in age-matched normotensive (n = 22) subjects and previously untreated patients (n = 19) with essential hypertension. 2. In all subjects the muscle fibres were classified, as fast-twitch (FT) and slow-twitch (ST), and blood pressure was recorded. Eleven patients and seven of the normotensive subjects participated in an extended haemodynamic study with intra-arterial pressure measurements and determinations of leg blood flow. 3. In both normo- and hyper-tensive subjects, ambulant and intra-arterial blood pressure and leg vascular resistance were negatively correlated to the percentage of ST fibres; no significant correlation was found to total leg blood flow. 4. The findings show that muscles with a high proportion of FT fibres have a higher resistance than muscles rich in ST fibres and suggest that the type of fibre in skeletal muscle might be of importance for the development of the hypertensive disease.

Serum concentrations of chloroquine were determined fluorometrically in 100 rheumatoid patients who had been treated with 0.25 gm daily for at least 2 mo. The total dose varied between 3.7 and 400 gm. No patient received more than 75 gm annually. In 15% of the patients side effects were noted. There was a relationship between serum concentrations and side effects but not with the total dose administered. Chloroquine displayed dose-dependent kinetics, which may indicate that close monitoring of serum concentrations is an aid to the safe and rational use of the drug.