Enantioselective determination of the hydroxylated metabolites of mexiletine in human plasma

Pre‐column derivatization with o‐phthaldialdehyde and N‐acetyl‐l‐cysteine was used for liquid‐chromatographic diastereomeric resolution of p‐hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), metabolites of mexiletine formed by aromatic and aliphatic hydroxylation, respectively. The resultin...

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Published in:Chirality (New York, N.Y.) N.Y.), 1997, Vol.9 (8), p.732-738
Main Authors: Lanchote, Vera Lúcia, Bonato, Pierina Sueli, Cesarino, Evandro José, Ali Mere Jr, Yussif, Cavani, Silvia Regina, Santos, Jorge, Bertucci, Carlo
Format: Article
Language:English
Subjects:
Anti-Arrhythmia Agents - blood
Chromatography, High Pressure Liquid
Circular Dichroism
diastereomer HPLC
Female
Humans
Hydroxylation
hydroxymethylmexiletine
Indicators and Reagents
Mexiletine - blood
Middle Aged
p-hydroxymexiletine
pharmacokinetics
plasma
Spectrometry, Fluorescence
Spectrophotometry, Ultraviolet
Stereoisomerism
validation
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Summary:Pre‐column derivatization with o‐phthaldialdehyde and N‐acetyl‐l‐cysteine was used for liquid‐chromatographic diastereomeric resolution of p‐hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), metabolites of mexiletine formed by aromatic and aliphatic hydroxylation, respectively. The resulting diastereomeric derivatives were resolved on a C18 column and monitored by fluorescence detection. The diastereomeric elution order for both metabolites was determined on the basis of the circular dichroism spectra of each eluted fraction. Plasma samples (500 μl) showed recoveries greater than 75% for both the metabolites. Calibration curves in plasma samples were linear over the concentration ranges 10–500 and 20–1,000 ng/ml for each enantiomer of PHM and HMM, respectively. The limits of quantitation were found to be 10.0 and 5.0 ng/ml for both enantiomers of PHM and HMM. The within‐day and between‐day coefficients of variation were less than 10%. The assay was shown to be suitable for a pharmacokinetic study performed in a patient with ventricular arrhythmias following the short‐term oral treatment of 200 mg t.i.d. of racemic mexiletine hydrochloride. Chirality 9:732–738, 1997. © 1997 Wiley‐Liss, Inc.
ISSN:0899-0042
1520-636X
DOI:10.1002/(SICI)1520-636X(1997)9:8<732::AID-CHIR4>3.0.CO;2-7