ENANTIOSELECTIVE DETERMINATION OF THE HYDROXYLATED METABOLITES OF MEXILETINE IN HUMAN PLASMA

Pre-column derivatization with o-phthaldialdehyde and N-acetyl-1-cyste ine was used for liquid-chromatographic diastereomeric resolution of p -hydroxymexiletine (PHM) and hydroxymethylmexiletine (HMM), metabolite s of mexiletine formed by aromatic and aliphatic hydroxylation, respec tively. The resulting diastereomeric derivatives were resolved on a C- 18 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 (50 0 mu l) showed recoveries greater than 75% for both the metabolites. C alibration 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 wit h ventricular arrhythmias following the short-term oral treatment of 2 00 mg t.i.d. of racemic mexiletine hydrochloride. (C) 1997 Wiley-Liss, Inc.