Selective LC-MS/MS determination of citalopram enantiomers and application to a pharmacokinetic evaluation of generic and reference formulations.

Two methods using LC-MS/MS were validated to quantify citalopram (CTP) racemate [(R/S)-CTP] and the enantiomers (R)-CTP and (S)-CTP in human plasma, respectively. Paroxetine hydrochloride was used as the internal standard, and samples were extracted by protein precipitation with acetonitrile. The non-enantioselective method was conducted using a C18 column, and the mobile phase consisted of water for solvent A and acetonitrile for solvent B, both with 0.1% formic acid. For the chiral method, an analytical column Lux Cellulose-1 was used. Mobile phase A was composed of water with 0.025% of formic acid and 0.05% of diethylamine, and mobile phase B consisted of acetonitrile:2-propanol (95:5, v/v). No significant matrix effects were observed at the retention times of analytes and internal standard. The mean recovery was 89%, and the assays were linear in the concentration range of 1-50 and 5-30 ng/mL for the non-enantioselective and enantioselective methods, respectively. The intra- and inter-day precisions of both methods were less than 12.30%, and the accuracies were less than 12.13%. The validated methods were successfully applied to a pharmacokinetic study in which 20-mg CTP tablets were administered to healthy volunteers, and their plasma levels were monitored over time in a bioequivalence study. HIGHLIGHTS: Simple and rapid LC-MS/MS method for the quantification of citalopram and its enantiomers in human plasma. Both methods were demonstrated to be selective, reliable, and sensitive. Both methods have sufficient sensitivity to quantify the steady state through concentrations already reported for citalopram and escitalopram. Validated method presented in this study can be suitably applied to pharmacokinetic studies involving citalopram and escitalopram. Bland-Altman analysis suggested that non-enantioselective and enantioselective methods can be applied in pharmacokinetic studies.

Rapid and sensitive method for simultaneous determination of citalopram with antihistamines by liquid chromatography.

A highly sensitive liquid chromatographic method with UV detection has been developed for simultaneous determination of citalopram, levocetirizine and loratadine in bulk drug, pharmaceutical formulation and human serum at 230nm employing 80:20 v/v methanol-water as mobile phase with pH3.5, adjusting flow rate of 1.0mL.min-1. Separation was achieved on Shimadzu Shim-pack CLC-ODS (M) 25M column within the linear range of 0.4-12.5, 0.8-25 and 0.8-25µg.mL-1 with R2 >0.998 and detection limit 7.75, 3.35 and 10.26ng.mL-1respectively. ICH guidelines were followed for validation showing 0.22-1.76, 0.06-1.83 and 0.22-2.11% RSD. The recovery of analytes in tablets and serum was found to be in acceptable range. The method was fruitfully employed for the determination of studied analyte in pharmaceutical formulation and human serum.

Planned complex suicide involving combined drug intoxication and femoral catheterization.

Complex planned suicide is characterized by the simultaneous use of two or more methods to ensure that death occurs even if one method fails. The authors present an original combination of two self-killing methods. A 42-year-old cardiologist, with a major depressive syndrome and several suicide attempts, as well as cocaine addiction, was found dead at his home with a femoral catheter inserted in the right femoral artery. The autopsy concluded that death was due to major hemorrhagic process in a context of suicide. Toxicological analyses, performed in peripheral blood by gas chromatography coupled to mass spectrometry and by liquid chromatography-diode array detection, revealed the presence of ethanol (0.13 g/L), cocaine, and metabolites (cocaine: 432 µg/L, benzoylecgonine: 3286 µg/L, ecgonine methyl ester: 1195 µg/L, cocaethylene: 41 µg/L), a potentially lethal concentration of citalopram (1.03 mg/L), toxic concentrations of hydroxyzine (0.11 mg/L), bromazepam (2.06 mg/L), and lidocaine (7.30 mg/L). At the end of these analyses, the death was reclassified as planned complex suicide combining drug intoxication and catheterization of the femoral artery. The authors discuss the main aspects of this case and stress the importance of meticulous analysis of all available evidence: witness reports, victim's medical history and occupation, findings of at-the-scene examination, autopsy, and toxicological analyses, in order to exclude homicide and to understand the sequence of events that led to death.

Gelatin microsphere coated Fe3O4@graphene quantum dots nanoparticles as a novel magnetic sorbent for ultrasound-assisted dispersive magnetic solid-phase extraction of tricyclic antidepressants in biological samples.

Gelatin microsphere-coated Fe3O4@graphene quantum dots (Fe3O4@GQD@GM) were designed and synthesized as a novel sorbent via ultrasonic-assisted dispersive magnetic solid-phase extraction (UA-DMSPE) method. The synthesized sorbent was identified and confirmed by FT-IR, XRD, VSM, and SEM techniques. UA-DMSPE was combined with corona discharge ion mobility spectrometry for trace determination of desipramine, sertraline, and citalopram. Effective parameters were considered and optimized. The proposed method, under optimal conditions, showed excellent linearity in different concentration ranges (2-700 ng mL-1, R2 > 0.995), repeatability (RSD < 5.1%), good sensitivity (LODs in the range 0.6-1.5 ng mL-1), high preconcentration factor (PF = 207-218), and acceptable relative recoveries (93.5-101.8%). Eventually, this method was used to determine tricyclic antidepressants in various biological samples. Schematic presentation of the microextraction and monitoring of TCAs by ultrasonic-assisted dispersive magnetic solid phase microextraction-ion mobility spectrometry producer.

Plasma Concentrations and Cardiovascular Effects of Citalopram Enantiomers After Oral Versus Infusion Citalopram Therapy in Dextromethorphan-Mephenytoin-Phenotyped Patients With Major Depression.

BACKGROUND: Authors compared plasma concentrations of citalopram (CIT) enantiomers and their metabolites in patients with depression administered either intravenously (IV) or as oral racemic CIT. Then, plasma concentrations were related to the metabolism of probes used for phenotyping patients with depression for CYP2C19 and CYP2D6 activity and cardiovascular functions. METHODS: Dextromethorphan-mephenytoin-phenotyped patients with depression were administered racemic CIT (days 1 and 2: 20 mg/d; days 3-10: 40 mg/d) either orally or as a slow-drop infusion for 10 days and were then orally administered the drug for another 32 days. Blood probes were collected at the time of minimal and maximal concentrations on day 10, immediately before and 2 hours after drug administration, and on days 21 and 42. Plasma CIT and its metabolites were assayed by stereoselective high-performance liquid chromatography. RESULTS: The following concentrations (ng/mL) were noted in the group receiving active IV infusion (IV-POS group, n = 27) of racemic CIT on day 10, before drug administration: escitalopram (S-CIT): 24 ± 10.2; R-citalopram (R-CIT): 45 ± 14.5; S-desmethyl-CIT: 13 ± 4.4; and R-desmethyl-CIT: 17 ± 8.2. In patients receiving oral administration (POS-POS group, n = 25), the values were 30 ± 12.7, 51 ± 17.4, 13 ± 4.6, and 17 ± 7.9 ng/mL, respectively. In the IV-POS group, 3 patients were poor dextromethorphan (CYP2D6) metabolizers; in the POS-POS group, one was a poor mephenytoin (CYP2C19) metabolizer. On day 10, before CIT treatment, S/R-CIT and S/R-mephenytoin ratios were significantly correlated, determined at baseline. Overall, CIT reduced the heart rate but did not significantly modify QTc. No relationship was found between any cardiovascular parameters and pharmacokinetic and pharmacogenetic data. CONCLUSIONS: Owing to CIT's high bioavailability, the plasma concentrations of its enantiomers remained largely independent on the administration route. CYP2C19 preferentially demethylated S-CIT after CIT therapy.

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.

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.

Escitalopram in Adolescents With Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018. METHODS: Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes. RESULTS: Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo. CONCLUSIONS: Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02818751.

A fatal case by a suicide kit containing sodium nitrite ordered on the internet.

Fatal sodium nitrite poisonings are rare in the forensic context. The present work describes a first fatal case of sodium nitrite contained in a suicide kit that the victim acquired over the internet. The results of the autopsy showed general signs of asphyxia, such as intense cyanosis of the extremities, brown-gray-blue-red livor mortis, and some Tardieu petechiae in addition to intense visceral congestion. It is clear that forensic experts must be aware of the proliferation of this market and the risks of improper selling of these substances through suicide support networks available on the internet. The lack of knowledge of this reality may become unidentifiable, when toxicological analysis contemplates only the most classical and frequent substances involved in poisoning and reinforce the importance of a careful analysis of the death scene.

Combinatorial Pharmacogenomic Algorithm is Predictive of Citalopram and Escitalopram Metabolism in Patients with Major Depressive Disorder.

Pharmacogenomic tests used to guide clinical treatment for major depressive disorder (MDD) must be thoroughly validated. One important assessment of validity is the ability to predict medication blood levels, which reflect altered metabolism. Historically, the metabolic impact of individual genes has been evaluated; however, we now know that multiple genes are often involved in medication metabolism. Here, we evaluated the ability of individual pharmacokinetic genes (CYP2C19, CYP2D6, CYP3A4) and a combinatorial pharmacogenomic test (GeneSight Psychotropic®; weighted assessment of all three genes) to predict citalopram/escitalopram blood levels in patients with MDD. Patients from the Genomics Used to Improve DEpression Decisions (GUIDED) trial who were taking citalopram/escitalopram at screening and had available blood level data were included (N=191). In multivariate analysis of the individual genes and combinatorial pharmacogenomic test separately (adjusted for age, smoking status), the F statistic for the combinatorial pharmacogenomic test was 1.7 to 2.9-times higher than the individual genes, showing that it explained more variance in citalopram/escitalopram blood levels. In multivariate analysis of the individual genes and combinatorial pharmacogenomic test together, only the combinatorial pharmacogenomic test remained significant. Overall, this demonstrates that the combinatorial pharmacogenomic test was a superior predictor of citalopram/escitalopram blood levels compared to individual genes.

Determination of atomoxetine or escitalopram in human plasma by HPLC: Applications in neuroscience research studies
.

BACKGROUND: Atomoxetine and escitalopram are potent and selective drugs approved for noradrenergic or serotonergic modulation of neuronal networks in attention-deficit hyperactivity disorder (ADHD) or depression, respectively. High-performance liquid chromatography (HPLC) methods still play an important role in the therapeutic drug monitoring (TDM) of psychopharmacological drugs, and coupled with tandem mass spectrometry are the gold standard for the quantification of drugs in biological matrices, but not available everywhere. The aim of this work was to develop and validate a HPLC method for neuroscientific studies using atomoxetine or escitalopram as a test drug. MATERIALS AND METHODS: A HPLC method from routine TDM determination of atomoxetine or citalopram in plasma was adapted and validated for use in neuroscientific research. Using photo diode array detection with UV absorption at 205 nm, the variation of internal standard within one chromatographic method enables separate drug monitoring for concentration-controlled explorative studies in healthy humans and patients with Parkinson's disease. RESULTS: The method described here was found to be linear in the range of 0.002 - 1.4 mg/L for atomoxetine and 0.0012 - 0.197 mg/L for escitalopram, with overall mean intra-day and inter-day imprecision and accuracy bias < 10% for both drugs. The method was successfully applied in concentration-controlled neuroimaging studies in populations of healthy humans and patients with Parkinson's disease. CONCLUSION: A simple, sensitive, robust HPLC method capable of monitoring escitalopram and atomoxetine is presented and validated, as a useful tool for drug monitoring and the study of pharmacokinetics in neuroscientific study applications.

A UPLC-MS/MS Assay for Simultaneous Determination of Two Antipsychotics and Two Antidepressants in Human Plasma and Its Application in Clinic.

BACKGROUND: Antidepressants and antipsychotics are widely prescribed drugs for the treatment of mental diseases. Therapeutic drug monitoring (TDM) is recommended for patients taking these drugs to ensure pharmaceutical efficacy, medication compliance and prevent toxicity. OBJECTIVE: An ultra-high performance liquid chromatography/tandem-mass spectrometry (UPLC-MS/ MS) method was developed for simultaneous determination of two Antidepressants-Fluoxetine (FLU) and Escitalopram (ESC), and two antipsychotics-risperidone (RIS) and aripiprazole (ARI), in human plasma. METHODS: The sample was processed by simple protein precipitation and the targeted analytes were separated on a C18 column by gradient elution with a mobile phase containing 0.1% formic acid (v/v) and acetonitrile. All the analytes were qualitative and quantitative measured by electrospray ionization source with Multiple Reaction Monitoring (MRM) in positive ion mode. A total of 56 plasma samples were obtained from out- or in-patients who were taking the cited four drugs for further analysis. RESULTS: The calibration curves for FLU, ESC, RIS and ARI were linear in the range of 45-1800, 4-320, 2-200 and 50-1800 ng/mL, respectively. The entire analytical time for the analytes was 7.0 min for each run and the extraction efficiency was more than 90%. The sample was stable within various storage conditions. The trough concentrations in patients were measured with the validated method. CONCLUSION: The developed method was successfully used for simultaneous determination of FLU, ESC, RIS and ARI in the plasma of the patients, which provides effective technical support for routine TDM of these four drugs and is of great clinic value for individual therapy.

Effects of Vortioxetine and Escitalopram on Electroencephalographic Recordings - A Randomized, Crossover Trial in Healthy Males.

The antidepressant drug vortioxetine has a multimodal action modulating neurotransmission through inhibition of the serotonin transporter and modulation of serotonin receptors. Vortioxetine has also been shown to alleviate cognitive symptoms in preclinical studies and in patients with depression. However, it is largely unclear how vortioxetine affects the brain processing in humans. The present study was conducted in 32 healthy males in a randomized, double-blinded, placebo-controlled, active comparator, four-way crossover design. Treatments were 10 and 20 mg/day vortioxetine, 15 mg/day escitalopram, and placebo, administered orally once daily for three days. Results were compared to placebo. Treatment effect was assessed by recording spontaneous electroencephalography (EEG) and 40 Hz auditory steady state responses. For the spontaneous EEG, both vortioxetine and escitalopram decreased the frequency content in the theta band (4-8 Hz) and increased power in the beta (12-32 Hz) and gamma (32-45 Hz) bands. Vortioxetine and escitalopram decreased connectivity during rest in the theta band and increased connectivity in the gamma bands. Finally, both treatments caused decreased power in the evoked gamma band in response to 40 Hz auditory stimulation. Although the global EEG changes were comparable between vortioxetine and escitalopram, subtle differences between treatment effects on the EEG in terms of effect size and regional distribution of the EEG changes were apparent. To our knowledge, the current results are the first data on how vortioxetine affects EEG in humans. The present study calls for further investigations addressing the possible electrophysiological and cognitive effects of vortioxetine.

Non-Fatal Intoxication with a High Dose of Citalopram in a Suicidal 14-Year-Old Girl.

The use of selective serotonin reuptake inhibitors (SSRIs) like citalopram in the clinical treatment of depressive symptoms in children and adolescents has become increasingly common, although application is mostly off-label. The increasing number of prescriptions is not only due to their good efficacy, but also due to their good tolerability and the comparatively low risk in cases of intoxication. However, there is discussion about the cardiac safety of overdose ingestion of citalopram. Here, we report in detail on an adolescent with depressive symptoms who used 800 mg of citalopram in order to attempt suicide. In contrast to other case reports in adults, our patient showed only mild neurological symptoms and no cardiac toxicity or symptoms of a serotonin syndrome, despite a high citalopram blood concentration measured about two hours following ingestion of citalopram (633 ng/ml; therapeutic reference range for adults 50-110 ng/ml).

Quantitation of escitalopram and its metabolites by liquid chromatography-tandem mass spectrometry in psychiatric patients: New metabolic ratio establishment.

Therapeutic drug monitoring (TDM) is used to determine the concentration of drug in plasma/serum to adjust the dose of the therapeutic drug. Selective and sensitive analytical methods are used to determine drug and metabolite levels for the successful application of TDM. The aim of the study was to develop and validate using LC-MS/MS to analyse quantitative assay of escitalopram (S-CT) and metabolites in human plasma samples. In order to provide a convenient and safe treatment dose, it was aimed to determine the levels of S-CT and its metabolites in the patients' plasma. A new method with short sample preparation and analysis time was developed and validated using LC-MS/MS to analyse quantitative assay of S-CT and its metabolites in plasma. Also, plasma samples of 30 patients using 20 mg S-CT between the ages of 18 and 65 years were analysed by the validated method. The mean values of S-CT, demethyl escitalopram and didemethyl escitalopram in plasma of patients were 27.59, 85.52 and 44.30 ng/mL, respectively. At the end of the analysis, the metabolic ratio of S-CT and metabolites was calculated. It is considered that the method for the quantitative analysis of S-CT and its metabolites in human plasma samples may contribute to the literature on account of its sensitive and easy application. Additionally, the use of our data by physicians will contribute to the effective drug treatment for their patients who take S-CT.

Development of bioanalytical HPLC method for simultaneous determination of the antialzhiemer, donepezil hydrochloride and the antidepressant, citalopram hydrobromide in raw materials, spiked human plasma and tablets dosage form.

OBJECTIVES: A novel, fast and sensitive HPLC method has been developed for the simultaneous bioanalytical determination of Donepezil hydrochloride (DON) and Citalopram hydrobromide (CTP) in raw materials, spiked human plasma and tablets. MATERIALS AND METHODS: Elution of both drugs was achieved with very good resolution using a RP-C18 chromatographic column, samples were analyzed using Hypersil Gold (100mm×4.6mm), 5µm particle size column and an isocratic binary mobile phase consists of phosphate buffer (0.05 M): acetonitrile (65:35). A Diode array detector at wavelength 232nm was used. Chromatographic separation was within a short run time (less than 7minutes) for both drugs. RESULTS: Retention times for DON and CTP were 4.5 and 5.8min, respectively. Linear calibration curves were obtained for DON and CTP over the concentration ranges of 0.1-10 and 0.1-50µg/mL. The mean extraction recoveries from spiked plasma were 93.22 and 92.64 for DON and CTP, respectively. The limits of detection and quantification were 0.017, 0.035µg/mL and 0.052, 0.106µg/mL for DON and CTP, respectively. CONCLUSION: The proposed method was successfully applied to the analysis of the cited drugs in raw materials, spiked human plasma and tablets with excellent accuracy and precision.

Serum and Saliva Concentrations of Venlafaxine, O-Desmethylvenlafaxine, Quetiapine, and Citalopram in Psychiatric Patients.

BACKGROUND: Therapeutic drug monitoring has become increasingly important in psychiatric therapy. However, it is not yet implemented as a daily routine in clinical settings. To evaluate new, noninvasive procedures, we compared blood and saliva venlafaxine, quetiapine, and citalopram concentrations in samples collected from psychiatric patients. METHODS: We collected blood and saliva samples from 75 psychiatric patients (39 venlafaxine, 19 quetiapine, and 17 citalopram). Saliva sampling was achieved by the use of cotton pads. Venlafaxine (and its metabolite O-desmethylvenlafaxine) and quetiapine were analyzed by LC-MS/MS, whereas citalopram was analyzed by HPLC. RESULTS: We observed significant correlations between concentrations of venlafaxine (ratio saliva/serum ± SD: 18.3 ± 9.5, P < 0.01, r = 0.895) and its metabolite O-desmethylvenlafaxine (ratio saliva/serum ± SD: 4.1 ± 3.2, P < 0.05, r = 0.344), quetiapine (ratio saliva/serum ± SD: 0.2 ± 0.2, P < 0.01, r = 0.935), and citalopram (ratio saliva/serum ± SD: 2.6 ± 1.2, P < 0.05, r = 0.54) in serum and in saliva. Furthermore, measured concentrations of venlafaxine (and its metabolite O-desmethylvenlafaxine) and citalopram were higher in saliva than in serum, whereas measured concentrations of quetiapine were higher in serum than in saliva. CONCLUSIONS: Using cotton pad saliva sampling, venlafaxine and quetiapine demonstrate high correlations between saliva and serum concentrations, whereas for O-desmethylvenlafaxine and citalopram, other methods of sampling might be preferable. Saliva therapeutic drug monitoring of psychoactive drugs might become a useful approach to achieving individual treatment regimens.

Suspected Driving Under the Influence Case Involving Mitragynine.

Mitragynine is a novel psychoactive substance (NPS) that has emerged as a designer opioid being distributed on the street. Mitragynine, also known as kratom, has dose-dependent pharmacological effects and possesses both stimulant-like and sedative effects due to dual-binding of α-adrenergic and µ-opioid receptors. This herbal remedy readily available online has caused adverse effects including tachycardia, agitation, tremors, hallucination and death; however, this is the first reported suspected driving under the influence case involving mitragynine. Additional testing outside of the normal routine protocol for suspected impaired driving cases was performed based on the admission of kratom use from the suspect to the drug recognition expert (DRE) officer. Based on the evaluation, the DRE officer concluded that the driver was under the influence of a central nervous system stimulant and cannabis. An alkaline drug screen identified mitragynine in a 37-year-old female driver who was suspected of driving under the influence after nearly striking an oncoming vehicle. A blood amphetamine concentration was quantified at 0.052 mg/L and mitragynine and citalopram were reported qualitatively. The goal of this case study is to provide demographic history, adverse effects and a DRE evaluation in a driver known to have abused mitragynine.

Effects of Cytochrome P450 (CYP) 2C19 Genotypes on Steady-State Plasma Concentrations of Escitalopram and its Desmethyl Metabolite in Japanese Patients With Depression.

BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using HPLC. CYP2C19 genotypes were identified using polymerase chain reaction methods. RESULTS: There were no differences in the steady-state plasma concentrations of escitalopram or desmethylescitalopram in each dose group (5, 10, 15, or 20 mg of escitalopram) among CYP2C19 genotype groups. However, 1-way analysis of variance showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram but not in the dose-adjusted plasma concentration of desmethylescitalopram. Analysis of covariance including age, sex, and body weight showed significant effects of CYP2C19 genotypes on the dose-adjusted plasma concentration of escitalopram and the ratio of desmethylescitalopram to escitalopram. CONCLUSIONS: These findings suggest that the CYP2C19 variants are associated with steady-state plasma concentrations of escitalopram to some extent but are not associated with desmethylescitalopram.

Phenotypic Assessment of Drug Metabolic Pathways and P-Glycoprotein in Patients Treated With Antidepressants in an Ambulatory Setting.

OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach. METHODS: From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5. RESULTS: We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent. CONCLUSIONS: The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02438072.