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

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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; Pn=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 (Pn=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 Pmax, but no significant change in Km, in MI compared to control livers (n=6). Intrinsic metabolic clearance (Vmax/Km) 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