Quinine distribution in mice with Plasmodium berghei malaria

The disposition of a single 80 mg/kg injection of quinine base was compared in control and Plasmodium berghei-infected mice. Pharmacokinetic parameters were determined on repeated whole blood samples from caudal vein (experiment 1) and quinine distribution was evaluated in tissues and blood fractions from mice sacrificed two hours post dosing (experiment 2). Quinine concentrations were assessed by high performance liquid chromatography with fluorometric detection. Whole blood concentrations and AUC(0 - infinity) of quinine increased in a parasitaemia-dependent manner. Quinine blood clearance and peak blood concentrations of metabolites negatively correlated with the parasitaemia. The apparent distribution volume of quinine only decreased in severely ill mice. Quinine concentrations rise in a parasitaemia-dependent manner in homogenates of spleen, lungs and kidney and in erythrocyte pellets. The negative relationship, observed between the parasitaemia and the tissue-to-whole blood ratio for muscle, heart, liver and brain, contributes to the reduction of the blood distribution volume. Quinine uptake by muscle and heart was dependent on the free fraction of plasma quinine. The liver and brain concentrations of quinine were similar in control and infected mice. The tissue-to-plasma free fraction ratios decrease when the parasitaemia rises suggesting a restrictive uptake of quinine by these tissues. In conclusion. P. berghei malaria decreases both total clearance and apparent volume of distribution with a heterogeneous redistribution of quinine between the tissues.