ASSESSMENT OF THE EFFECT OF MALARIA INFECTION ON HEPATIC-CLEARANCE OFDIHYDROARTEMISININ USING RAT-LIVER PERFUSIONS AND MICROSOMES

1 The clearance of dihydroartemisinin (DHA) in control and malaria-inf ected (MI) rats was investigated using the isolated perfused rat liver (IPRL) model and hepatic microsomal studies. 2 In the recirculating I PRL, clearance of DHA was reduced from a mean (s.d.) of 8.2+/-1.8 mi m in(-1) in controls (n=8) to 6.0+/-1.0 mi min(-1) in MI (n=8; P<0.01). Clearance in control livers was similar to the perfusion flow rate, su ggesting a high hepatic extraction ratio for DHA. 3 Single-pass IPRL s tudies in controls (n=8) showed that DHA. bioavailability at 1.3, 8 an d 38 mu M was 0.026+/-0.020, 0.043+/-0.025 and 0.14+/-0.06, respective ly (P<0.001 for 8 mu M vs 38 mu M). In MI livers (n = 5), DHA bioavail ability at 8 and 38 mu M was 0.18+/-0.07 and 0.40+/-0.08, respectively (P=0.002). Bioavailability was higher in the MI group than in control s (P=0.01 at 8 mu M and P<0.001 at 38 mu M). DHA-glucuronide was the s ole biliary metabolite. 4 Hepatic microsomal studies of DHA-glucuronid e formation showed a significantly lower V-max, but no significant cha nge in K-m, in MI compared to control livers (n=6). Intrinsic metaboli c clearance (Vmax/Km) was higher in control than in MI livers (5.2+/-1 .3 and 2.5+/-1.4 mu l min(-1) mg(-1), respectively; P = 0.006). 5 Thes e studies demonstrate that DHA has a high, concentration-dependent hep atic extraction ratio that is reduced by 20-30% in the P. berghei rode nt malaria model. The impaired hepatic clearance of DHA in MI is attri butable to a reduction in intrinsic metabolic clearance.