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Doxepin, a tricyclic antidepressant (TCA), is widely used in the treatment of depressive disorder and anxiety. There are some liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods that have been reported for detecting doxepin, but inadequacies in recovery and cumbersome sample preparation obstruct the pharmacokinetics study. Therefore, we aimed to develop and validate a rapid sample preparation method based on solid-phase extraction (SPE) for the precise quantification of doxepin and its metabolites. Chromatography separation was performed on a Waters ACQUITY UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) and a mobile phase consisting of 70% of mobile phase A (0.1% formic acid and 10 mM ammonium formate) and 30% mobile phase B (0.1% formic acid in acetonitrile) at a flow rate of 0.4 mL min -1 in the step gradient elution conditions. The lower limits of quantification for doxepin and N -nordoxepin were 4 pg mL -1 and 2 pg mL -1 , respectively. This method was validated with satisfactory results including good precision and accuracy. A rapid, sensitive, and specific LC-MS/MS method was developed and validated for the determination of doxepin in human plasma. This method could be applied for determining doxepin and N -nordoxepin concentrations in plasma that could be useful for bioequivalence study of 3 mg doxepin.

The aim of this study was to establish a high-throughput and sensitive LC-MS/MS method for the determination of doxepin and its major active metabolite nordoxepin in human plasma. It has been designed for bioequivalence study for formulations containing 25 mg of doxepin. Doxepin and nordoxepin were extracted from human plasma samples by protein precipitation with acetonitrile by using protein precipitation 96-well plates. The analyte was separated using a Phenomenex Kinetex Biphenyl column (100 × 2.1 mm, 2.6 μm) using isocratic elution with a mobile phase of 20 mM ammonium formate (30%) and acetonitrile:methanol 3:7 v:v (70%) at a flow rate of 0.5 mL/min and an injection volume of 10 μL. The detection was performed using a triple quadrupole mass spectrometer by multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 280.4 → 107.0 and 283.4 → 235.0 for doxepin and doxepin-D3, respectively, and 266.3 → 106.9 and 269.3 → 235.0 for nordoxepin and nordoxepin-D3, respectively, in positive electrospray ionization mode. The total run time was 3.5 min. The method was validated over a concentration range of 50-10,000 pg/mL using a Triple Quad 4500 MS System (Sciex) for both analytes. The developed and validated method can be successfully used to study the bioequivalence/pharmacokinetics of doxepin and nordoxepin., (© 2020 John Wiley & Sons, Ltd.)

Perhexiline is a drug that is used for treatment of moderate to severe angina pectoris that has not responded to other treatment. It has a low therapeutic index, and saturable metabolism that is also subject to genetic polymorphism (CYP2D6). Concentration monitoring of the parent drug and its major metabolite is considered necessary to optimise efficacy and reduce the risk of hepatotoxicity and neuropathy. A rapid, simple and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) assay was developed for the determination of perhexiline and its metabolite cis-hydroxyperhexiline in human plasma. After proteins were precipitated with acetonitrile, perhexiline, the major metabolite cis-hydroxyperhexiline and nordoxepin as the internal standard were resolved on a phenyl-hexyl column using gradient elution of 0.05% formic acid and methanol. The three compounds were detected using electrospray ionisation in the positive mode. Standard curves were linear over the concentration range 10-2000microg/L (r>0.999), bias was