Pharmacokinetics of Chloroquine and Some of Its Metabolites in Healthy Volunteers: A Single Dose Study

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Abstract
Eight healthy volunteers who had not taken chloroquine 2 to 12 months previously participated in a single dose study designed to evaluate the pharmacokinetics of chloroquine and some of its metabolites. Each subject received two tablets of chloroquine sulfate (300 mg base) only. Blood and urine samples were collected just before and periodically after chloroquine administration. These samples were assayed for chloroquine and its N-dealkylated metabolites (monodesethylchloroquine, didesethylchloroquine, 7-chloro-4-aminoquinoline), chloroquine side chain N-oxide and chloroquine di-N-oxide using a high performance liquid chromatographic method. Residual levels of chloroquine and its N-oxidation metabolites were found in all subjects. 7-chloro-4-aminoquinoline was eliminated more slowly (t½z = 126.48 ± 20.13 h) than the other metabolites and the unchanged drug (t½z = 106.43 ± 10.13 h). Also, 7-chloro-4-aminoquinoline had a significantly faster (Student's t-test, P < 0.05) formation clearance when compared with the other metabolites. The plasma concentration of 7-chloro-4-aminoquinoline was about twice that of the unchanged drug while the plasma concentration of monodesethylchloroquine was about 46% that of the unchanged drug. In order to investigate whether the metabolites were produced from the same binding sites or closely related sites on the cytochrome P-450 system, their formation clearances were correlated. The best correlation (r2 = 0.83) was observed for didesethylchloroquine and monodesethylchloroquine, and a fair correlation (r2 = 0.59) was observed for monodesethylchloroquine and 7-chloro-4-aminoquinoline. Formation clearances of the other metabolites were poorly correlated. The N-dealkylated metabolites of chloroquine are of pharmacological and toxicological importance. It may, therefore, be necessary to monitor their plasma concentrations in addition to that of chloroquine in patients on long-term chloroquine therapy.