Toxicity Profile, Pharmacokinetic, and Drug–Drug Interaction Study of Citalopram and Sertraline Following Oral Delivery in Rat: An LC-MS/MS Method for the Simultaneous Determination in Plasma

Abstract

The burden of depression and other mental disorders is on the rise globally, and successful treatment sometimes requires modifications of drugs and/or dose regimens. The development of novel analytical methods for the determination of antidepressant drugs in biological fluids is thus urgently required. Herein, a sensitive, robust, and rapid liquid chromatographic coupled tandem mass spectrometric method was developed and validated for the determination of citalopram (CIT) and sertraline (SER) in rat plasma after oral administration. The analytes of interest and internal standard (duloxetine (DUL)) were extracted from 100 μL of plasma with solid-phase extraction on an Oasis HLB cartridge followed by the separation with gradient elution with water containing 0.1% formic acid and acetonitrile on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 μm) column at flow rate 0.2 mL min −1 . The triple quadrupole mass spectrometry was applied via electrospray ionization source for detection. The fragmentation pattern of the protonated CIT, SER, and DUL was elucidated using multiple reaction monitoring of the transitions of m/z 325.2 to 109, 306.1 to 158.9, and 298.1 to 154.1 as [M + H] + for CIT, SER, and DUL, respectively. The proposed method has been validated as per US-FDA bioanalytical guidelines in terms of linearity, accuracy, precision, matrix effects, stability, selectivity, and recovery. The method was linear over the concentration range of 1−2000 and 1−1000 ng mL −1 with the lower limit of detection of 0.12 and 0.19 ng mL −1 for CIT and SER, respectively. The interday and intraday precisions and accuracy expressed by the relative standard deviation and the relative standard error were both lower than 11.1% and 2.1%, respectively. The proposed method was successfully applied for the pharmacokinetics and drug monitoring studies of CIT and SER in rat plasma after a single oral dose of 120 mg kg −1 of CIT and SER. Coadministration of SER with CIT has affected the peak plasma concentrations, maximum plasma concentration time, area under the concentration−time curve, and oral clearance of CIT. Molecular modeling study showed that SER could competitively inhibit CYP2D6, the main enzyme involved in CIT metabolism. A possible drug−drug interaction in psychiatric patients undergoing chronic SER and CIT treatment is therefore worthy of more attention in an effort to avoid side effects and serotonin syndrome.

Recent Advances in Analytical Techniques for Antidepressants Determination in Complex Biological Matrices: A Review

“…Protein precipitation, 26,48,58,59 LLE, 15,25,29,41,46,53,60 SPE, 12,17,[20][21][22][23]28,32,34,36,42,51,56,59,62,64 and some miniaturized techniques-such as SPME, 33 MEPS, 30,50,54 DLLME, 14 AA-DLLME, 27 BAμE, 24 and LPME 13 are the most utilized procedures for extracting antidepressants from the biological samples.…”

“…As mentioned above, biospecimens where antidepressants are usually detected include urine, 24,51,53-55,61,64,65 whole blood, 11,17,22,23,29,31,35,36,39,41,57,58 dried blood spots, 11,32 plasma, 23,26,28,48,48,60,63 serum, 23,40,46,50,63,65 hair, 44,51 OF, 30,62,67 pericardial fluid, 14 bone marrow, 33,52,66 bones, 21,25,34,47,59 brain tissue, 36 intraosseous fluid, 26 meconium, 56 and VH 12,13 with each matrix requiring specific treatment depending on the type of antidepressant under investigation.…”

“…Elgawish et al (2020) 28 employed solid-phase extraction (SPE) in combination with liquid chromatography-tandem mass spectrometry (LC/MS/MS) technique to determine antidepressant drugs, sertraline, and citalopram levels in plasma samples (rat) after oral administration of a single-dose of 40 mg/kg of sertraline and citalopram. The linear range of this method for citalopram and sertraline was 1-2000 and 1-1000 ng/mL, with lower limits of detection (LLOD) of .35 and .18 ng/mL, respectively.…”

Self-assembled ruthenium decorated electrochemical platform for sensitive and selective determination of amisulpride in presence of co-administered drugs using safranin as a mediator

“…Depression is considered as a common mental disorder, which influences over 264 million people worldwide and becomes a critical health problem; approximately 800,000 persons have been died because of suicide every year [1]. Recently, the psychiatric consequences of the covid-19 infections to manifest are receiving high attention [2].…”