Kinetics and prophylactic efficacy of increasing dosages of liposome-encapsulated chloroquine after intramuscular injection into mice

Abstract

Abstract Chloroquine (CQ) levels in blood, heart, liver, spleen and kidney as a function of time were determined after intramuscular (i.m.) injection of increasing amounts (0.64,1.32,1.98,2.63 and 3.30 mg) of liposome-encapsulated chloroquine (lip-CQ) to mice. Maximum CQ concentration in blood (Cmax), area under the curve ( AUC ), mean residence time (MRT) and the absorption rate constant (ka) were determined. The prophylactic efficacy of lip-CQ was studied in Plasmudium berghei-infected mice. Parasitaemia was determined after single infection and repeated infection of the mice. CQ concentrations in blood could be monitored during at least 8 days (0.64 mg lip-CQ) up to 15 days ( 3.30 mg lip-CQ ). AUC and MRT values initially increased with dose and finally reached a plateau value, whereas ka values initially decreased and finally reached a plateau value at higher dosages. Mean Cmax values decreased with the dose. The prophylactic efficacy of lip-CQ increased with the dose. After intramuscular administration of 0.64 mg lip-CQ and infection one week later, all mice developed infection. When 3.30 mg was administered no mice developed infection when parasites were injected 7 days later and 83% and 33% of mice remained negative when parasites were injected 14 and 21 days respectively, after injection of the lip-CQ depot. CQ concentrations in heart were low in all cases which is favorable regarding cardiotoxicity of the drug. The CQ content of spleen, liver or kidney either 15 h or 24 h after injection of lip-CQ was independent of dosage. No dose dependency in chloroquine content, neither 24 h nor 15 days after injection was observed in spleen, liver or kidney. Within the range tested, injection of higher doses of lip-CQ exhibit a prolonged and a comparatively slower release of CQ. This is probably caused by mechanical compaction of the liposomal depot by the surrounding tissue. Prophylactic efficacy increased with the lip-CQ dose.