Pharmacokinetics of the diastereomers of arteether, a potent antimalarial drug, in rats

The pharmacokinetics of alpha- and beta- diastereomers of arteether, a potent erythrocytic schizontocidal agent, and their active metabolite dihydroartemisinin were studied in male Sprague-Dawley rats after oral, intramuscular and intravenous administrations. Oral and intramuscular studies were carried out at three dose levels at 9, 17.5 and 30 mg kg(-1). The ratio of alpha- and beta-isomers was maintained at 30:70% w/w in the formulations used for the study. The average oral bioavailabilities of alpha-and beta-isomers, relative to intramuscular administration, were 9.6% and 3.8%, respectively, and the average in vivo alpha- to beta- ratio was 2.5. Following intravenous and intramuscular administrations the in vivo alpha- to beta- ratios were 0.7 and 0.9, respectively. The beta-isomer of arteether was characterized by a longer elimination half-life and a relatively larger volume of distribution than the alpha-isomer, suggesting that beta-arteether may be responsible for the prolonged in vivo schizontocidal activity. The alpha-isomer was absorbed rapidly after oral and intramuscular administrations and showed higher peak plasma concentrations but possessed a relatively shorter half-life. There was an apparent lack of linearity observed in terms of dose and AUCs for both alpha- and beta-arteether after oral and intramuscular administrations, suggesting nonlinear dose dependent pharmacokinetics at the dose levels studied. The rate and extent of conversion of arteether isomers to dihydroartemisinin was highest with oral and intravenous administration and least with intramuscular indicating that the intramuscular route of administration of the isomeric mixture may be more beneficial for malarial chemotherapy.