Assessment of the effect of malaria infection on hepatic clearance of dihydroartemisinin using rat liver perfusions and microsomes

Abstract

1. The clearance of dihydroartemisinin (DHA) in control and malaria-infected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2. In the recirculating IPRL, clearance of DHA was reduced from a mean (s.d.) of 8.2 ± 1.8 ml min-1 in controls (n = 8) to 6.0 ± 1.0 ml min-1 in MI (n = 8; P < 0.01). Clearance in control livers was similar to the perfusion flow rate, suggesting a high hepatic extraction ratio for DHA. 3. Single-pass IPRL studies in controls (n = 8) showed that DHA bioavailability at 1.3, 8 and 38 μM was 0.026 ± 0.020, 0.043 ± 0.025 and 0.14 ± 0.06, respectively (P < 0.001 for 8 μM vs 38 μM). In MI livers (n = 5, DHA bioavailability at 8 and 38 μM was 0.18 ± 0.07 and 0.40 ± 0.08, respectively (P = 0.002). Bioavailability was higher in the MI group than in controls (P = 0.01 at 8 μM and P < 0.001 at 38 μM). DHA-glucuronide was the sole biliary metabolite. 4. Hepatic microsomal studies of DHA-glucuronide formation showed a significantly lower V(max), but no significant change in K(m), in MI compared to control livers (n = 6). Intrinsic metabolic clearance (V(max)/K(m)) was higher in control than in MI livers (5.2 ± 1.3 and 2.5 ± 1.4 μl min-1 mg-1, respectively; P = 0.006). 5. These studies demonstrate that DHA has a high, concentration-dependent hepatic extraction ratio that is reduced by 20-30% in the P. berghei rodent malaria model. The impaired hepatic clearance of DHA in MI is attributable to a reduction in intrinsic metabolic clearance.