The effect of malaria infection on primaquine elimination in the isolated perfused rat liver

Abstract

Most antimalarial drugs are eliminated by hepatic metabolism. However, the influence of malaria infection on the hepatic elimination of these drugs has not been examined. In the present study the elimination of the antimalarial primaquine has been examined in isolated perfused rat livers (IPRL) of malaria-infected Sprague-Dawley rats (90–110 g) (MI group; N = 6) and age- and weight-matched healthy rats (control group; N = 7). IPRL preparations for the MI group were established 12–15 days after rats were infected with merozoites of Plasmodium berghei (150 × 10 6 parasites/ml; 0.2ml i.p.). At the time of study there was marked variation in the degree of parasitaemia achieved in the rats used m the MI group, from 2 to 27% of erythrocytes being infected. Livers were isolated using standard techniques and perfused at 10 ml/min in a 100 ml recycling system for 4 hr. In the control group, the perfusate disappearance of primaquine was biphasic with a mean t 1 2 β of 0.77±0.10 hr . This was prolonged in the MI group (mean t 1 2 β = 1.06 ± 0.09 hr; P < 0.05 ). There was no significant difference in the volumes of distribution of primaquine between the MI group (mean = 320 ± 73 ml) and the control group (mean = 284 ± 79 ml). Although there was a trend to lowered primaquine clearance in the MI group (mean 217 ± 26ml/hr), it was not significantly different from that seen in the control group (mean = 277 ± 42 ml/hr; 0.10 < P > 0.05). However, there was an inverse linear correlation between primaquine clearance and the percentage parasitaemia (r = 0.722, P < 0.05). These results suggest that the extent to which primaquine elimination had been compromised was related to the severity of malaria infection, and that in severe infections reduced efficiency of elimination raises the possibility of drug toxicity.