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

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 μ M was 0.026±0.020, 0.043±0.025 and 0.14±0.06, respectively ( P <0.001 for 8 μ M vs 38 μ M ). In MI livers ( n =5), DHA bioavailability at 8 and 38 μ M 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 μ M and P <0.001 at 38 μ M ). 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.British Journal of Pharmacology (1998) 125 , 159–167; doi: 10.1038/sj.bjp.0702023