Tissue and blood concentrations of chloroquine following chronic administration in the rat.

The antimalarial drug, chloroquine, is extensively distributed in tissue and slowly eliminated such that after a single dose, a plasma half-life of 3-5 days has been found (McChesney & McAuliff 1961; McChesney et al 1967). A peak tissue/plasma concentration ratio greater than 300 is obtained in many tissues and after a single dose the drug can be found in the liver and urine for up to five years (Gaudette & Coatney 1961; Rubin et al 1963; Zvaifler et al 1963). Chronic administration of chloroquine for the treatment of rheumatoid arthritis has revealed an ocular toxicity due to accumulation of the drug in the pigmented layers of the eye, particularly the choroid (Fuld & Horwish 1958; Fuld 1959). A more recent indication for chronic administration of chloroquine is in the prophylaxis of malaria, for which the drug is administered at a dose of 300-600 mg weekly to adults. The long term toxic effects of chloroquine when administered in this way are unknown but no ocular toxicity has been reported even after five years of such use. Since tissue toxicity and other untoward effects are largely determined by tissue stores (Fuld & Horwish 1958; Fuld 1959) and blood levels (Laaksonen et al 1974; Frisk-Holmberg et al 1979) of the drug, it is useful to know the changes occurring in tissue and plasma concentrations during chronic administration. Previous studies in animals have given conflicting results. McChesney et al (1965) found a steady increase in the tissue and plasma concentrations in rats throughout a 3-month period although the increase was fastest in the first month. Grundmann et al (1972) found that most rat tissues were saturated with chloroquine between the 10th and the 16th weeks. Plasma concentrations were not measured hence the effect of tissue saturation on blood levels was not determined, yet saturation of tissue stores would be expected to lead to a rapid increase in plasma concentration that could affect the pattern and incidence of adverse reactions to the drug. We have reinvestigated the uptake of chloroquine by rat tissues during chronic administration of the drug and in particular to relate the tissue levels to plasma concentrations.