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

Abstract

Aim: 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. Results: 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. Conclusion: 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.