Pharmacokinetics of chloroquine diphosphate in the dog.

Chloroquine diphosphate was administered i.v. and orally to seven male beagle dogs. Approximately 2 mg/kg was administered i.v. and 4 weeks later a single 150-mg (tablet) dose was administered orally. Blood sampling was carried out for 28 and 42 days, respectively, and whole blood drug levels were assayed by fluorometry. After i.v. injection, the chloroquine blood concentration-time profile exhibited a biexponential decay. The mean terminal T 1/2 was 12.6 days using i.v. data alone and 14.5 days with simultaneous fitting of oral and i.v. data. Pharmacokinetic parameters calculated using model-independent methods showed good agreement with model-dependent methods. The model-independent value for blood clearance was 2.67 liters/kg/day. A mean Vdss of 53.3 liters/kg indicates that the drug is widely distributed to tissues. Using a specific thin-layer chromatographic method, chloroquine and its major metabolite, desethylchloroquine, could be detected in blood for 42 days after oral chloroquine administration. These data suggest a long T 1/2 for the metabolite, as well as the parent drug. Chloroquine, desethylchloroquine and bisdesethylchloroquine were tested for in vitro activity against clinically derived chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Against chloroquine-sensitive P. falciparum, desethylchloroquine was as active as chloroquine, whereas bisdesethylchloroquine was less active. Against a chloroquine-resistant strain, desethylchloroquine was less active than chloroquine and bisdesethylchloroquine possessed no detectable activity.