The Effect of Fever on Quinine and Quinidine Disposition in the Rat

Abstract— The pharmacokinetics of quinine and its diastereoisomer quinidine has been investigated in normal and febrile rats. Endotoxin‐induced fever in rats resulted in an increased quinine clearance (CL) (4·49 ± 1·45 vs 1·38 ±0·65 L h−1 kg−1, P < 0001) and volume of distribution (Vd) (42·6 ± 8·8 vs 28·9 ± 10·3 L kg−1, P < 0·05) with a concomitant shortening of the elimination half‐life (t½) (7·1 ±2·5 vs 15·9 ± 5·9 h, P < 0·01). With quinidine, however, fever resulted in an increased CL (3·95 ± 1·05 vs 1·89 ± 0·60 L h−1 kg−1, P < 0·002) with no change in Vd and a significant decrease in t½ (5·1 ±0·7 vs 10·1 ±2·8 h, P < 0·001). In both studies there was no significant difference in hepatic microsomal protein or cytochrome P450 content. Neither drug accumulated in the liver but low concentrations of quinidine were present in the heart 24 h after administration. In‐vitro studies suggest that temperature does not alter the binding of either drug. These data suggest that fever enhances the clearance of quinine and quinidine. These findings may offer some additional explanation of the lack of serious quinine and quinidine toxicity during the treatment of malaria infection, even after large dosages of the drug administered during the initial period of treatment when fever is most intense. 1991 Royal Pharmaceutical Society of Great Britain