Systematic Method Developlvient For The Determination Of Artemether And Its Met Abolite Dihydroartemisinin
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Date
1996-03
Authors
Chin, Lee Kean
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Abstract
Two assay methods were developed for the plasma measurement of artemether. The
first one is based on a liquid-liquid extraction of the drug by isooctane with a high
performance liquid chromatography coupled with ultra violet (HPLC-UV) detection at
211 nm. However the lowest detectable limit with confidence for artemisinin and
artemether is 20 and 60 ng on column. It is realised that this method has a relatively
low sensitivity but a reasonable accuracy above the limits of detection. It should suffice
for assessing therapeutic drug monitoring but not suitable for routine analysis of blood
samples in pharmacokinetic studies. For measurement of drug concentrations below
the limits of detection by the HPLC -UV method, a selective and reproducible high
peri()(Jl1HnCe liquid clllolllatography coupled with an ciectrochelllical detection
(HPLC-ECD) assay for the simultaneous quantitative determination of the antimalarial
compounds artemether, dihydroaI1emisinin and artemisinin, as internal standard is
described After extraction from plasma, artemether and dihydroartemisinin were
analysed using a Lichrocart/Lichrosphere 100 eN stainless steel column and a mobile
phase of acetonitrile 0.05M acetic acid (15 85 v/v) adjusted to pH 5.0, and
electrochemical detection in the reductive mode. The mean recovery of artemether
and dihydroartemisinin over a concentration range of 30-120 ng/ml was 99.62% and
99.39% respectively The within-day coefficients of variati<n were 0.89-7.01 % for
artemcther and 3.45-8.11 % for dihydroartemisinin. The day-to-day coetllcients of
variation were 2.06-8.43% and 6.33-8.22% respectively. The minimum detectable
concentration in plasma was 5 ng/mg for both compounds. The method was found to
be suitable for lise in clinical pharmacological studies. The maximum blood
concentration (Cmax) of 422.5 ng/ml of a preliminary pharmacokinetic profile after a
single administration of artemether to a healthy Malaysian volunteer was reached 1.75
hOllrs following drug administration, and the area under curve (AUC) was 654 ng/ml.
The plasma clearance (CI), apparent volume of distribution (Vd) and elimination halflife
(tll2) were 3060 mllmin, 282L and 1.06 hour respectively. Dihydroartemisinin
reached Cmax of3868 ng/ml, 1.75 hr upon administration oC artemether with an area
under curve (AUC) of 604 nghr/mL CI, V d and t 112 values for this metabolite were
3310 IImin, 296 Land l. 03 hr respectively.
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Keywords
Two assay methods were developed for , the plasma measurement of artemether