The validation of an LC-MS/MS assay for perhexiline and major hydroxy metabolites, and its application to therapeutic monitoring in patient plasma.

Abstract

Perhexiline (PEX), being developed to treat hypertrophic cardiomyopathy, is toxic at levels above the therapeutic range. Plasma level monitoring is therefore essential. The absence of a UV-absorbing chromophore has in the past required quantitative analysis of PEX in plasma using lengthy derivatization methods, followed by HPLC and fluorescence detection. The routine and urgent analysis of a large number of patient plasma samples necessitates faster and reliable analytical methodology. An LC-MS/MS method, using two novel internal standards, has been validated for the quantitative measurement of PEX and its major hydroxy metabolites in human plasma. The assay has been applied to therapeutic drug monitoring (TDM), where PEX and the ratio of the drug to cis-hydroxy perhexiline, were measured at designated intervals.