Autoinduction of phase I and phase II metabolism of artemisinin in rats

Abstract

1. This study was designed to get the direct evidence of the autoinduction metabolism for the antimalarial drug artemisinin (QHS). The sex effect on the pharmacokinetic profiles of QHS and its metabolites was also studied.

2. Two groups of rats received a single oral dose of QHS, and another two groups of rats were given oral doses of QHS once daily for 5 consecutive days. Plasma samples and its phase I and phase II metabolites were analysed for QHS, using a validated liquid chromatography tandem mass spectrometric (LC-MS) method.

3. Eight phase I metabolites (DQHS, M1–M7) and five phase II metabolites (M8–M12) of QHS were detected in rat plasma. The AUC_0−t of the parent drug QHS, and its phase I metabolites DQHS, M2, M3 and M6 decreased significantly (p < 0.05) with increased oral clearance (CL/F) (p < 0.05) after 5-day oral doses of QHS to rats. There was no change (p > 0.05) in AUC of M1 and M4, whereas its metabolites M5 and M7 exhibited higher AUC (p < 0.05). The AUC of phase II metabolites M8, M11 and M12 also increased after multiple oral doses of QHS. Sex difference was observed for QHS and its metabolites DQHS, M1, M3, M5, M8 and M9 in rats after a single oral dose of QHS.

4. The results gave the direct evidence for the autoinduction of both phase I and phase II metabolism of QHS. The sex effect existed for QHS.

Keywords::

• Artemisinin
• metabolites
• autoinduction
• sex difference