Support of Study Entitled, 'Metabolism and Pharmacokinetics of Dihydroartemisinin' and 'In Vitro and In Vivo Metabolism of Sodium Artelinate and DQHS in Rats and Humans'

摘要

The following is a report on our study to identify the metabolites of artelinic, an artemisinin (qinghaosu) derivative being developed for uncomplicated malaria. Identification of the metabolites of artelinic acid and other artemisinin analogues has been problematic because of the unavailability of standards of the putative metabolites. The following report presents our attempts to prepare the putative metabolites of artelinic acd by reacting artelinic acid with chemical systems that may simulate the activity of the cytochrome P-450 system. Standards of possible metabolites of artelinic acid were produced by the reaction of artelinic acid with complexes of iron(II) and manganese(II) that may simulate cytochrome P-450 catalysed metabolism of xenobiotics. The standards were used to identify metabolites formed on incubation of artelinic acid with human liver microsomes. The metabolism of artelinic acid by human liver microsomes involved isomerization/rearrangement involving the endoperoxide group, C-hydroxylation and debenzylation to dihydroqinghaosu (DQHS), an important active metabolite. Debenzylation of artelinic acid to DQHS is mediated by CYP3A4.