IDENTIFICATION OF THE GLUCURONIDES OF THE HYDROXYLATED METABOLITES OFTHE ANTIMALARIAL ARTEETHER IN RAT PLASMA AND URINE BY THERMOSPRAY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY
K. Ramu et Jk. Baker, IDENTIFICATION OF THE GLUCURONIDES OF THE HYDROXYLATED METABOLITES OFTHE ANTIMALARIAL ARTEETHER IN RAT PLASMA AND URINE BY THERMOSPRAY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY, Journal of pharmaceutical sciences, 86(8), 1997, pp. 915-920
A method was developed to quantitate the glucuronide conjugates (phase
II metabolites, log P = 0.6-1.8) of the phase I hydroxylated metaboli
tes (log P = 2.6-2.7) of beta-arteether (2) (log P = similar to 4.0) i
n rat plasma and urine. The biological fluids were extracted with a C-
18 solid-phase cartridge, then subjected to analysis by thermospray hi
gh-performance liquid chromatography/mass spectroscopy with a C-18 rev
ersed-phase analytical column in the selected ion monitoring mode. The
detection limits for these glucuronide conjugates in plasma and urine
ranged from 25 to 60 ng/mL, and the detection limits were appropriate
for the biological activity of these glucuronide conjugates in plasma
. Following intravenous administration of arteether (11.6 mg/kg), the
formation of these glucuronide conjugates in rat urine was undetected
(below detection limit) over 24 h. However, in rat plasma, formation o
f 9 alpha-hydroxyarteether glucuronide (13; 255 ng/mL, IC50 = 6560 ng/
mL, log P = 0.93) was noted at 15 min post-injection. Although several
of the glucuronide metabolites of arteether retained sufficient in vi
tro antimalarial activity to be potentially useful antimalarial agents
it administered as prodrugs, the levels of the glucuronides formed fr
om arteether were too low to contribute to the antimalarial activity o
bserved for the parent compound.