Abstract
BackgroundDihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. So far, however, the tissue distribution and metabolic profile of DHA data are not available from animal and humans.MethodsPharmacokinetics, tissue distribution, mass balance, and elimination of [14C] DHA have been studieded in rats following a single intravenous administration. Protein binding was performed with rat and human plasma. Drug concentrations were obtained up to 192 hr from measurements of total radioactivity and drug concentration to determine the contribution by the parent and metabolites to the total dose of drug injected from whole blood, plasma, urine and faecal samples.ResultsDrug was widely distributed after 1 hr and rapidly declined at 24 hr in all tissues except spleen until 96 hrs. Only 0.81% of the total radioactivity was detected in rat brain tissue. DHA revealed a high binding capacity with both rat and human plasma proteins (76–82%). The concentration of total radioactivity in the plasma fraction was less than 25% of that in blood total. Metabolism of DHA was observed with high excretion via bile into intestines and approximately 89–95% dose of all conjugations were accounted for in blood, urine and faeces. However, the majority of elimination of [14C] DHA was through urinary excretion (52% dose). The mean terminal half-lives of plasma and blood radioactivity (75.57–122.13 h) were significantly prolonged compared with that of unchanged DHA (1.03 h).ConclusionIn rat brain, the total concentration of [14C] was 2-fold higher than that in plasma, indicating the radioactivity could easily penetrate the brain-blood barrier. Total radioactivity distributed in RBC was about three- to four-fold higher than that in plasma, suggesting that the powerful anti-malarial potency of DHA in the treatment of blood stage malaria may relate to the high RBC binding. Biliary excretion and multiple concentration peaks of DHA have been demonstrated with high urinary excretion due to a most likely drug re-absorption in the intestines (enterohepatic circulation). The long lasting metabolites of DHA (> 192 hr) in the rats may be also related to the enterohepatic circulation.
Highlights
Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades
Pharmacokinetics of [14C] DHA and unchanged DHA Pharmacokinetic parameters calculated from mean levels of total radioactivity and unchanged DHA in either whole blood or plasma are shown in Table 1 after single i.v. administration of [14C] DHA
Unchanged DHA was completely eliminated within 6 hr after 5–6 half-lives (Table 2), indicating that the long-lasting metabolites of DHA (> 192 hr) in the rats may be related to slow release of DHA binding from RBC or other tissues with subsequent metabolism and the enterohepatic circulation
Summary
Dihydroartemisinin (DHA), a powerful anti-malarial drug, has been used as monotherapy and artemisinin-based combination therapy (ACT) for more than decades. Artesunate is a more potent anti-malarial drug than arteether and artemether, which may be explained by the conversion to DHA with the DHA/AS ratios of 0.31–2.74 in animal species [6,7], and 2.81–9.71 in malaria humans [8,9]. A study demonstrated that only DHA was rapidly effective against all stages of the parasite life cycle and completely inhibited the parasite growth within the shortest exposure time when compared to all other artemisinin drugs [10]. It is felt by many clinicians that AS administered intravenously is the most effective for treatment of severe malaria due to the high DHA levels [11]
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