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.

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