EFFECTS OF PLASMODIUM-BERGHEI INFECTION ON ARTEETHER METABOLISM AND DISPOSITION

Arteether (AE) is primarily deethylated to dihydroqinghaosu (DQHS) in rats and humans. Conversion of AE to DQHS was impaired in microsomes f rom rats infected with Plasmodium berghei. The K-m for AE was 175.1 +/ - 49.1 and 124.4 +/- 115.1 mu mol/l, and V-max was 2.24 +/- 0.45 and 1 .22 +/- 0.67 nmol AE formed/mg protein/min in control and infected mic rosomes (p < 0.05), respectively, Calculated intrinsic clearance (CLin t = initial V-max/K-m) for AE was only 4% lower in infected microsomes . Apparent pharmacokinetic parameter estimates for AE using the isolat ed perfused rat liver demonstrated no differences (p > 0.05) in volume of distribution, clearance, and half-life between normal and infected animals. Malaria infection resulted in decreased biliary excretion of free AE and DQHS. The majority of AE is eliminated via biliary excret ion of conjugated DQHS, which is approximately 500-fold higher than fr ee DQHS and 75-fold higher than free AE on a molar basis.