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A simple dried blood spot method for therapeutic drug monitoring of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, clomipramine, and their active metabolites using LC-MS/MS

2014; Elsevier BV; Volume: 134; Linguagem: Inglês

10.1016/j.talanta.2014.10.041

1873-3573

E.J.J. Berm, J. Paardekooper, E. Brummel-Mulder, Eelko Hak, Bob Wilffert, Jan Gerard Maring,

Antibiotics Pharmacokinetics and Efficacy

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8 min. The assay was linear in the range 20–500 µg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and 15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method.