An investigation of the auto-induction of and gender-related variability in the pharmacokinetics of dihydroartemisinin in the rat

Artemisinin (QHS) and its derivatives dihydroartemisinin (DHA), artemether and artesunate have become the first-line anti-malarials in areas of multidrug resistance. Declining plasma concentrations during the repeated dosing have been reported for QHS, artemether and less convincingly for artesunate (ARS). However, there is limited information on whether the concentrations of their active metabolite DHA and its subsequent metabolites increased after multiple drug administrations. This study was designed to evaluate the potential auto-induction metabolism of DHA in animal species. The sex-specific effect on the pharmacokinetic profiles of DHA and its metabolites was studied. The pharmacokinetics of ARS, the prodrug of DHA, and its phase I/II metabolites were also investigated.

The results gave the direct evidence for the absence of auto-induction of phase I and phase II metabolism of DHA and ARS in rats. The sex effect existed for DHA but not for ARS, which could be caused by the sex-specific differences in absorption of DHA.

Two groups of rats received a single oral dose of DHA or ARS, and another two groups of rats were given oral doses of DHA or ARS once daily for five consecutive days. Plasma samples were analyzed for DHA, ARS and their phase I/II metabolites, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.

DHA, monohydroxylated DHA (M1) and the glucuronide of DHA (DHA-G) were detected in rat plasma after oral administration of DHA or ARS. Neither DHA nor its metabolites (M1 and DHA-G) changed significantly (P > 0.05) in AUC0-t after 5-day oral doses of DHA or ARS. Sex difference was observed for DHA and its metabolites (M1 and DHA-G), whereas its prodrug ARS did not show similar characteristics for the corresponding metabolites (DHA, M1 and DHA-G). Conclusions: The results gave the direct evidence for the absence of auto-induction of phase I and phase II metabolism of DHA and ARS in rats. The sex effect existed for DHA but not for ARS, which could be caused by the sex-specific differences in absorption of DHA.