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Practical LC-MS/MS method for the simultaneous quantification of amitriptyline, nortriptyline and their hydroxy-metabolites in human serum.

Amitriptyline has been in use for decades in depression and more recently for the management of neuropathic pain. A highly sensitive and specific LC-MS/MS method was developed for simultaneous determination of amitriptyline [AMI], its active metabolite nortriptyline [NOR] and their hydroxy-metabolites in human serum, using deuterated AMI and NOR as internal standards. The isobaric E-10-hydroxyamitriptyline [E-OH AMI], Z-10-hydroxyamitriptyline [Z-OH AMI], E-10-hydroxynortriptyline [E-OH NOR] and Z-10-hydroxynortriptyline [Z-OH NOR], together with their parent compounds, were separated on an ACE C-18 column using a simple protein precipitation method, followed by dilution and analysis using positive electrospray ionization with multiple reaction monitoring (MRM). The total run time was 6 minutes with elution of E-OH AMI, E-OH NOR, Z-OH AMI, Z-OH NOR, AMI (+ deuterated AMI) and NOR (+ deuterated NOR) at 1.21, 1.28, 1.66, 1.71, 2.50, 2.59 min respectively. The method was validated in human serum with a lower limit of quantitation of 0.5 ng/mL for all analytes. A linear response function was established for the range of concentrations 0.5 - 400 ng/mL (r2 > 0.999). The practical assay was applied on samples from patients on amitriptyline, genotyped for CYP2C19 and CYP2D6, to understand the influence of metaboliser status and concomitant medication on therapeutic drug monitoring.