The multiple-dosing pharmacokinetics of artemether, artesunate, and their metabolite dihydroartemisinin in rats.

1. The present study was designed to investigate the multiple-dosing pharmacokinetics of antimalarial drugs artemether (ARM), artesunate (ARS), and their metabolite dihydroartemisinin (DHA) in rats. 2. Rats were randomized into four groups. Two groups of rats received oral doses of ARM or ARS once daily for five consecutive days. And another two groups of rats were given a single oral dose of ARM or ARS. Plasma samples were analysed for artemisinin drugs and their active metabolite DHA, using a validated liquid chromatography/tandem mass spectrometric (LC/MS/MS) method. 3. ARM and ARS could be biotransformed to metabolite DHA almost immediately after oral administration to rats. The area under the plasma concentration-time curve (AUC(0-t)) of ARM after 5-day oral doses significantly decreased from 50.3 to 23.4 ng × h/mL (P < 0.05), and oral clearance (CL/F) of ARM increased from 10.5 to 27.2 L/min/kg (P < 0.05). The AUC(0-t) of its metabolite DHA of ARM significantly decreased from 42.1 to 16.4 ng × h/mL (P < 0.05), and its CL/F increased from 11.7 to 33.4 L/min/kg (P < 0.05). The 5-day oral doses of ARS did not result in significant changes (P > 0.05) in pharmacokinetic parameters of ARS, whereas its metabolite DHA exhibited lower AUC (P = 0.05), compared with that obtained after a single oral administration. 4. The results showed ARM and its metabolite DHA exhibited time-dependent pharmacokinetic characteristics with decreased plasma drug level after five consecutive days of oral administration to rats, whereas ARS and its metabolite DHA did not show similar characteristics.