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Background: Given the importance of achieving optimal therapeutical concentration in patients treated with antidepressants, this study investigates a novel technique for the simultaneous determination of trazodone (TRZ) and doxepin (DOX) in human plasma and serum samples for the first time., Results: To achieve simultaneous determination of two antidepressants, TRZ and DOX, a novel detection system was designed: a non-enzymatic voltammetric biosensor based on boron-reduced graphene oxide/manganese oxide nanoparticles (GCE/B-rGO/MnO NPs). The detection was accomplished after pre-concentration and extraction trace amounts of the analytes using the thin film-solid phase microextraction (TF-SPME) technique, which employed polyvinyl alcohol/polyvinyl acetate/copper oxide nanoparticles (PVA/PVAc/CuO NPs) electrospun nanofibers. The successful preparation of composite nanofibers and modified electrodes was confirmed using the evaluation of field emission-scanning electron microscopy (FE-SEM) and energy-dispersive X-ray spectroscopy (EDX). Also, the composite nanofibers were characterized with attenuated total reflectance-Fourier transform-infrared (ATR-FT-IR) and X-ray diffraction (XRD). In the solution of TRZ and DOX, under optimum experimental conditions, the linear dynamic ranges (LDRs) were 0.1-20.0 μmol L -1 and 0.5-27.0 μmol L -1 , respectively. Also, the limit of detection (LOD) values of TRZ and DOX were 0.032 and 0.150 μmol L -1 ., Significance: PVAc acts as a cross-linking agent for PVA, and their mixture is effective for sample preparation and pre-concentration of analytes in complex matrices. Also, adding CuO NPs to this polymeric mixture enhanced the adsorption efficiency. Taking advantage of the high surface area of MnO NPs and the high electrical conductivity of B-rGO, and considering the superiority of their simultaneous utilization, the constructed electrochemical biosensor is both cost-effective and rapid. It demonstrates excellent stability, repeatability, and sensitivity for the simultaneous determination of TRZ and DOX under optimal conditions. This biosensor, the first of its kind, is specifically designed for the simultaneous determination of TRZ and DOX in human plasma and serum samples, representing a significant advancement in biosensing technology., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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.)

A novel solid-phase microextraction fiber was synthesized by coating a stainless steel wire with polyoxomolybdate 368 /polyaniline as a sorbent aimed at extraction of amitriptyline, nortriptyline, and doxepin as antidepressant drugs from urine and blood samples. The polyoxomolybdate 368 /polyaniline composite coating was applied using electropolymerization process under constant potential. This composition leads to enhanced extraction efficiency of the fiber. Scanning electron microscopy images show that huge three-dimensional structures of polyoxomolybdate 368 in composite induced more non-smooth and porous fiber. In order to optimize of the extraction process, a series of variables including concentration of the composite materials, coating thickness, pH, extraction time, salt addition, and stirring rate was investigated and optimum conditions were determined. Analysis of surface morphology and chemical composition was performed. High-performance liquid chromatography was used for separation and evaluation of mentioned antidepressant drugs from the matrixes. The experiments indicated a detection limits of <0.2 ng/L and a linear dynamic range of 0.3-100 ng/L (R 2  > 0.994). The relative recovery values were found to be in the range of 92-98%. It was concluded that the purposed fiber is highly efficient in analyzing traces of antidepressant drugs in urine and blood., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Tricyclic antidepressants have been shown to affect electrocardiogram (ECG) parameters, but there is limited evidence in relation to the serum concentrations. Therefore, we aimed to evaluate a prediction of cardiac risk in amitriptyline- and doxepin-treated patients by serum concentrations., Patients and Methods: The association between serum concentrations of amitriptyline (n = 100) and doxepin (n = 71) and ECG parameters was retrospectively examined using linear regression analysis. Mann-Whitney U tests were applied to evaluate differences in QTc intervals in patients with serum concentrations above and below the upper limit of the therapeutic reference range, as well as the alert level of each target drug., Results: The sum serum concentration of amitriptyline and the nortriptyline serum concentration were significantly associated with an increased PQ interval (p = 0.020, p = 0.007), as well as with increased QTcB (p = 0.012, p < 0.001) and QTcF intervals (p = 0.025, p < 0.001). The nortriptyline concentration was significantly associated with the QRS interval (p = 0.003). In patients with active moiety concentrations above the alert level (300 ng/ml) and nortriptyline concentrations above the reference range (170 ng/ml), the QTcB interval was significantly prolonged (p = 0.032, p = 0.007). No significant association with any ECG parameter was detected for doxepin serum concentrations., Conclusion: The effect of amitriptyline on ECG parameters may be explained by nortriptyline alone. Accordingly, with increasing nortriptyline concentrations, the potential risk for an atrioventricular block, a bundle branch block, and prolongation of QTc interval may increase significantly.

In this work, molecularly imprinted nanoparticles (MINPs) were applied as selective adsorbent for ultrasound-assisted micro-solid-phase extraction (UAMSPE) of doxepin (DP) from human plasma samples, which was then cleaned up, pre-concentrated and subjected to HPLC. The MINPs were synthesized based on a non-covalent approach by precipitation polymerization utilizing methacrylic acid and styrene as functional monomers, DP as template, ethylene glycol dimethacrylate as cross-linker and 2,2-azobisisobutyronitrile (AIBN) as initiator. The obtained MINPs were characterized by Fourier transform-infrared and field emission scanning electron microscopy. Factors influencing the efficiency of UAMSPE such as sonication time, volume of eluent solvent and amount of sorbent were investigated using a central composite design and the optimal points were identified as 4 min of sonication time, 380 μL of eluent solvent and 30 mg of sorbent. Under optimized conditions, the proposed method has linear responses in the range of 0.2-2000 ng mL -1 , with a satisfactory limit of detection of 0.04 ng mL -1 and limit of quantification of 0.11 ng mL -1 ., (© 2019 John Wiley & Sons, Ltd.)

Smoking is common among psychiatric patients and has been shown to accelerate the metabolism of different drugs. We aimed to determine the effect of smoking on the serum concentrations of psychopharmacological drugs in a naturalistic clinical setting. Dose-corrected, steady-state serum concentrations of individual patients were analyzed retrospectively by linear regression including age, sex, and smoking for amitriptyline (n=503), doxepin (n=198), mirtazapine (n=572), venlafaxine (n=534), clozapine (n=106), quetiapine (n=182), and risperidone (n=136). Serum levels of amitriptyline (P=0.038), clozapine (P=0.02), and mirtazapine (P=0.002) were significantly lower in smokers compared with nonsmokers after correction for age and sex. In addition, the ratios of nortriptyline/amitriptyline (P=0.001) and nordoxepin/doxepin (P=0.014) were significantly higher in smokers compared with nonsmokers. Smoking may not only induce CYP1A2, but may possibly also affect CYP2C19. Furthermore, CYP3A4, UGT1A3, and UGT1A4 might be induced by tobacco smoke. Hence, a different dosing strategy is required among smoking and nonsmoking patients. Nevertheless, the clinical relevance of the results remained unclear.

Background: To uncover pharmacokinetic interactions between venlafaxine and doxepin or mirtazapine in a naturalistic sample., Methods: A therapeutic drug monitoring database containing plasma concentrations of venlafaxine (VEN) and its active metabolite O-desmethylvenlafaxine (ODVEN) was analyzed. We included 1067 of 1594 patients in the analysis. Three study groups were considered; a group of patients under venlafaxine without confounding medications, V 0 (n = 905), a group of patients co-medicated with doxepin, V DOX (n = 25) and a second group, co-medicated with mirtazapine, V MIR , n = 137. Plasma concentrations of VEN, ODVEN and the clinically relevant active moiety, sum of venlafaxine and O-desmethylvenlafaxine (ODVEN) (AM), as well as dose-adjusted plasma concentrations (C/D) were compared., Results: Median concentrations in the doxepin group showed 57.7% and 194.4% higher values for AM and VEN respectively; these differences were statistically significant (p < 0.001 for AM and p = 0.002 for VEN). Similar differences were detected for C/D concentrations of active moiety and VEN (p < 0.001 and p = 0.001) with higher values also in the doxepin group. The ratios ODVEN/VEN were lower in the doxepin group (p < 0.001). A co-medication with mirtazapine did not cause any changes in venlafaxine metabolism., Conclusions: Higher concentrations for VEN and AM imply an inhibiting effect of doxepin on the metabolism of venlafaxine, although the huge variability of concentrations has to be taken into account. It is recommended to monitor plasma concentrations in combination treatment to avoid problems in safety and efficacy., Limitations: Despite the large size of our study sample, the naturalistic nature of this data may arise some concerns of information bias potentially resulting from non-standardized data recording., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this work, a novel polythiophene/graphene oxide (PTh/GO) nanostructured coating was introduced for on-line electrochemically-controlled in-tube solid phase microextraction of amitriptyline (AMI) and doxepin (DOX) as antidepressant drugs. The PTh/GO coating was prepared on the inner surface of a stainless steel tube by a facile in-situ electro-deposition method and it was used as a working electrode for electrochemically control in-tube solid phase microextraction. In the PTh/GO coating, GO acts as an anion dopant and sorbent. The PTh/GO coating, compared to PTh and GO coatings, exhibited enhanced long lifetime, good mechanical stability and a large specific surface area. Regarding the in-tube SPME, some important factors such as the extraction and desorption voltage, extraction and desorption times and flow rates of the sample solution and eluent, which could affect the extraction and separation efficiency of the analytes, were optimized. Total analysis time of this method including the online extraction and desorption time was about 21min for each sample. AMI and DOX were extracted, separated and determined with limits of detection as small as 0.3μgL -1 and 0.5μgL -1 , respectively. This method showed good linearity in the range of 0.7-200μgL -1 , 2.3-200μgL -1 and 2.9-200μgL -1 for AMI, and in the range 0.9-200μgL -1 , 2.5-200μgL -1 and 3.0-200μgL -1 for DOX in water, urine and plasma samples, respectively; the coefficients of determination were also equal to or higher than 0.9976. The inter- and intra-assay precisions (RSD%, n=3) were in the range of 2.8-3.4% and 2.9-3.9% at the three concentration levels of 5, 25 and 50μgL -1 , respectively. Finally, under the optimal conditions, the method was applied for the analysis of the drugs in human urine and plasma pretreated samples and good results were obtained., (Copyright © 2016. Published by Elsevier B.V.)

The differentiation of intoxication courses is one of the most difficult challenges for forensic pathologists and toxicologists. The case of a 52-year-old female inpatient of a psychiatric clinic with multiple medications who died from doxepin intoxication is reported. Concentrations of doxepin metabolites and isomers, pharmacokinetic modelling and genotyping of the doxepin-metabolizing cytochrome P450 (CYP) enzymes led to the following conclusion: the lethal doxepin concentration of 2100 ng/mL was more likely to have been reached due to drug interactions and genetic peculiarities leading to a reduction of the metabolic capacity and not by an acute (suicidal) overdose., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

In the present work, electromembrane surrounded solid phase microextraction (EM-SPME) is introduced for the first time. The organic liquid membrane, which consists of 2-nitrophenyl octyl ether (NPOE), was immobilized in the pores of a hollow fiber (HF) and the basic analytes migrated in an electrical field from aqueous sample solution through the liquid membrane and into aqueous acceptor phase and then they were adsorbed on the solid sorbent, which acts as the cathode. Effective parameters such as composition of organic liquid membrane, pH of donor and acceptor phases, applied voltage and extraction time were optimized for extraction of amitriptyline (AMI) and doxepin (DOX) as model analytes and figures of merit of the method were investigated in pure water, human plasma, and urine samples. To extract the model analytes from 24 mL neutral sample solution across organic liquid membrane and into aqueous acceptor phase, 120 V electrical potential was applied for 20 min and finally the drugs were adsorbed on a carbonaceous cathode. Regardless of high sample cleanup, which make the proposed method suitable for the analysis of drugs from complicated matrices, extraction efficiencies in the range of 3.1-11.5% and good detection limits (less than 5 ngmL(-1)) with admissible repeatability and reproducibility (intra- and inter-assay precisions ranged between 4.0-8.5% and 7.5-12.2%, respectively) were obtained from different extraction media. Linearity of the method was studied in the range of 2.0-500.0 ngmL(-1) and 5.0-500.0 ngmL(-1) for AMI and DOX, respectively and coefficient of determination higher than 0.9947 were achieved. Finally, the proposed method was applied for the analysis of AMI and DOX in real samples., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To develop a method of SPE-LC-MS/MS for the determination of doxepin in whole blood., Methods: After solid phase extraction, the samples were identified by LC-MS/MS. Positive ion electrospray ionization mode and multiple reaction monitoring (MRM) mode was selected. Amitriptyline was used as internal standard. The m/z of doxepin: 280-->107, 280-->235 and 280-->220. The m/z of amitriptyline: 278-->233. The retaining time of doxepin and amitriptyline were 15.15 and 16.94 min, respectively., Results: The calibration curve was linear among the concentration of doxepin range from 0.005 to 1.00 microg/mL. The linear correlation equation was y = 3.2047x + 0.0339, the correlation coefficient was 0.9996. The detection limit of doxepin was 0.001 microg/mL and average recovery rate was 78.0%-82.9%. The relative standard precision for within-day and between-day were less than 2.55% and 5.90%, respectively., Conclusion: The method is effective, simple, reliable and can be used in the determination of doxepin in whole blood.

Doxepin--like other antidepressant drugs (ADs)--shows a variable antidepressant effect in clinical practice. The cause for this variability is as yet unclear; however, pharmacokinetic factors such as the variable permeability of doxepin into the cerebrospinal fluid (CSF), may contribute to the difference in therapeutic efficacy. We measured and correlated the concentration of doxepin and its active metabolite nordoxepin in both the plasma and CSF. Plasma and CSF samples were taken simultaneously from 21 patients who were treated with doxepin due to different clinical indications. The plasma concentration of both doxepin and nordoxepin correlated significantly with the oral dosage of doxepin (doxepin: r = +0.66, p < 0.001; nordoxepin: r = +0.78, p < 0.0001; Spearman's correlation). Furthermore, we found significant correlations between the plasma and CSF concentrations of both doxepin (r = +0.71; p < 0.001; Pearson's correlation) and nordoxepin (r = +0.74; p < 0.001). These highly significant correlations between the plasma and CSF concentrations indicate a constant CSF permeability of doxepin and its active metabolite nordoxepin.

Objective: Intoxication with antidepressants, frequently encountered in pediatric emergency medicine, can often lead to life threatening situations. While hyperthermia, hypertonicity and rigidity are symptoms indicative of a serotonin syndrome triggered by an intoxication with serotonin reuptake inhibitors or monoamine oxidase inhibitors, cardiotoxicity, coma and ECG changes are typical of an intoxication with tricyclic antidepressants., Case Report: Hypothermia (instead of the expected hyperthermia) is described for the first time as a persistent symptom during the course of a combined moclobemide-doxepin intoxication in an attempted suicide of a 16-year-old adolescent., Discussion: The administration of serotonin reuptake inhibitors alone or in combination with other medication which increases the level of 5-hydroxytryptamine, i.e. serotonin, in the synaptic cleft mainly leads to hyperthermia. According to a recent study, however, the application of a selective 5-HT(1a) agonist to transgenic mice with a prominent overexpression of the 5-HT(1a) receptor lead to immobility and hypothermia. These findings might help to explain the hypothermia observed in the case of the intoxicated 16-year-old., Conclusion: Intoxication with antidepressants should not be excluded a priori in a hypothermic patient who displays other clinical signs of the said intoxication., (2009. Published by Elsevier Ireland Ltd.)

The problems concerning an unstable data basis with regard to lethal Doxepin concentrations have been manifested based on a case about a 39-year-old man, who was found dead in his apartment with strangulation marks on his neck, for which a lethal Doxepin intoxication entered the differential diagnosis discussion. For a long time it has been known that postmortem redistribution leads to a falsely inflated concentration as measured in cardiac blood, while the concentrations in peripheral postmortem blood change comparatively little. Despite this, most of the current literature relies on published case report, which fails to mention the location of blood sampling, whereby it is fairly safe to assume that a central sample is intended. Only 9 cases of an isolated lethal Doxepin intoxication have been found, in which the concentrations in blood samples from peripheral vessels had been measured. These values lie between 1.5 and 7.0 mg/L, which is in the lowest quarter of the span of lethal concentrations mentioned in literature without specific mention of the location of the blood sample.

It has been suggested that the polymorphism of the CYP2D6 gene can contribute to occurrence of fatal adverse effects. We therefore investigated postmortem toxicology cases of fatal drug poisonings related to CYP2D6 substrates, with the manner of death denoted as accidental or undetermined. CYP2D6 genotypes were determined in 11 consecutive cases with samples available for DNA analysis. A case of fatal doxepin poisoning with an undetermined manner of death was found to coincide with a completely nonfunctional CYP2D6 genotype (*3/*4), indicating a total absence of CYP2D6 enzyme and suggesting a poor metabolizer phenotype. The doxepin concentration was 2.4 mg/L, the concentration of nordoxepin 2.9 mg/L, and the doxepin/nordoxepin ratio 0.83, the lowest found among the 35 nordoxepin-positive postmortem cases analyzed during the same year. No alcohols or other drugs were detected in the case. The CYP2C19 genotype was determined as that of an extensive metabolizer. The high N-desmethylmetabolite concentration is not consistent with acute intoxication. It is therefore probable that the defective genotype has contributed to the death, possibly involving repeated high dosage of doxepin. Our case strongly emphasizes that a pharmacogenetic analysis in postmortem forensic setting may reveal new insight to the cause or manner of death.

A 48-year-old woman with a major depression and treatment with doxepin was found comatose in her flat. Her son last saw her 48 h prior to being found. On arrival of the emergency physician, she presented a generalized seizure. The patient underwent endotracheal intubation and mechanical ventilation due to respiratory insufficiency and severe cyanosis. Empty packages of tablets (doxepin ca. 4000 mg and zolpidem 100 mg) were found in the flat. On hospital admission the doxepin blood concentration was 1.2 microg/ml. No life-threatening arrhythmia occurred at any time. On the advice of the poison information center, hemoperfusion was performed for extracorporeal elimination. Within several hours the doxepin blood concentration could be lowered to 0.8 microg/ml and although still above the therapeutic range the patient was extubated. However, the patient developed a generalized seizure which required re-intubation. As a consequence of the high distribution volume and re-distribution phenomena, the doxepin blood concentration had increased again to 1.2 microg/ml. Approximately 72 h later she was extubated again while the doxepin blood concentration was 0.9 microg/ml and 3 days later, the doxepin blood concentration was lowered to 0.3 microg/ml and the patient was transferred to the psychiatric ward the following day. This case report questions the efficacy of hemoperfusion during acute doxepin intoxication in the given constellation of a non-life-threatening arrhythmia.

Objective: To develop a specific, sensitive, reproducible SPE-HPLC method for the determination of 37 drugs in whole blood., Methods: With the doxapram as internal standard, Oasis column was used to extract drugs from whole blood. Two kinds of mobile phases were used in this study. Separations were achieved by a LiChrospher 100 RP-C18 (250 mm x 4.0 mm x 5 microm) column kept at 50 degrees C, the DAD detector was set at 230 nm and 250 nm., Results: The limit of detection were 1-30 ng/mL. The method showed excellent linearity and the linear correlation coefficient was > or =0.997 98. The relative standard deviation for between-day and within-day assay were <10%., Conclusion: The method is effective, simple, reliable and has been used in real cases.

This paper reports a simple and reliable gas chromatographic method with nitrogen-phosphorus detection without derivatization for the simultaneous detection of fluvoxamine, mianserin, doxepin, citalopram, paroxetine, and etoperidone in whole blood as part of a systematic toxicological analysis (STA). All drugs were studied at concentration levels of 100-2000 ng/mL, except paroxetine for which it was necessary to study at concentration levels of 400-8000 ng/mL. A comparative and validation study using two solid-phase extraction (SPE) columns, Chem Elut and Bond Elut Certify, was developed regarding their recovery, precision, sensitivity, and matrix purification efficiency. The Chem Elut columns, diatomaceous earth, are closely related to conventional liquid-liquid extraction. The Bond Elut Certify columns, more recently developed in the market, are mixed SPE (reversed-phase and cation exchange sorbent). Recoveries for the antidepressants using Chem Elut columns at 500 ng/mL (2000 ng/mL for paroxetine) were in the range 43-72% with intra- and interassay precisions of less than 10% and 16%, respectively. Limits of detection (LODs) and quantitation (LOQs) for fluvoxamine, mianserin, doxepin, citalopram, and etoperidone ranged from 18 to 236 ng/mL and 60 to 786 ng/mL, respectively. LOD and LOQ for paroxetine were 303 and 1009 ng/mL, respectively. Recoveries of these compounds using Bond Elut Certify columns at 500 ng/mL (2000 ng/mL for paroxetine) were in the range 52-83% with intra- and interassay precisions of less than 6% and 8%, respectively. LODs and LOQs for fluvoxamine, mianserin, doxepin, citalopram, and etoperidone ranged from 7 to 28 ng/mL and 23 to 93 ng/mL, respectively. LOD and LOQ for paroxetine were 113 and 376 ng/mL, respectively. An excellent linearity was observed with both procedures from the LOQs up to the upper studied concentration level. In general, higher recoveries, cleaner extracts, better sensitivity, better precision, and reduced solvent consumption and disposal were achieved for the screening of these antidepressants with the use of the mixed SPE Bond Elut Certify compared with Chem Elut columns. The application of these methods on a forensic case study is also presented.

Background: Mice with a genetic disruption (knockout) of the multiple drug resistance (abcb1ab) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein (P-gp) at the blood-brain barrier on the uptake of the antidepressants venlafaxine, paroxetine, mirtazapine, and doxepin and its metabolites into the brain., Methods: One hour after subcutaneous injection of venlafaxine, paroxetine, mirtazapine, or doxepin, knockout and wildtype mice were sacrificed, and the drug concentrations in brain, spleen, kidney, liver, and plasma were measured., Results: The cerebrum concentrations of doxepin, venlafaxine, and paroxetine were higher in knockout mice, demonstrating that these substances are substrates of P-gp and that abcb1ab activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, brain distribution of mirtazapine was indistinguishable between the groups., Conclusions: The differences reported here in brain penetration of antidepressant drugs that depend on the presence of the abcb1ab gene may offer an explanation for poor or nonresponse to antidepressant treatment. Furthermore, they may be able to explain in part the discrepancies between plasma levels of an antidepressant and its clinical effects and side effects.

A novel diltiazem HCl extended-release (ER) tablet formulation was developed for evening administration in the management of angina and hypertension. Pharmacokinetics of the formulation were evaluated to identify variations in morning (7 a.m. or 8 a.m.) versus evening (10 p.m.) drug administration. Single-dose (360 mg) and multiple-dose (360 mg once daily for 7 days), open-label, randomized, two-way crossover studies of the new diltiazem HCl ER tablets were completed in 48 healthy volunteers. Serial plasma samples were collected via direct venipuncture up to 48 hours postdose and analyzed for diltiazem and its two major metabolites by high-performance liquid chromatography (HPLC). The primary parameters used to assess the data were AUC0- infinity, AUC0-tau, AUC6 a.m.-12 p.m., Cmax, and tmax. Statistical comparisons using ANOVA were evaluated after logarithmic transformation of dose-dependent parameters. Diltiazem HCl ER tablets administered in the evening exhibited 17% and 22% greater bioavailability compared to morning administration under single-dose and steady-state conditions, respectively. The two times of drug administration were bioinequivalent in both studies. The evening schedule also provided more than twofold higher plasma diltiazem levels in the critical morning hours, when both blood pressure and the incidence of cardiovascular events are the highest.

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCA) is established in the treatment of depression to optimize outcome and safety. However, there are few reports on TDM under naturalistic clinical conditions. In the present study, we investigated a TDM group (TDM) and a randomly assigned parallel group without TDM (no-TDM) while on TCA treatment. Serum levels were analyzed in both cohorts, but feedback and dose recommendation were only provided for the TDM group. Serum levels of TCA were assessed by high-performance liquid chromatography (HPLC). The outcome was measured weekly using the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impressions Scale (CGI), and the UKU side-effect scale. 84 patients with depressive disorder according to DSM-IV were recruited in three centers (TDM, n = 43; no-TDM, n = 41; mean age 49.9 +/- 13.2 years, 63.1 % female). Patients were treated with either amitriptyline (n = 69) or doxepin (n = 15); the mean dosage at endpoint was 126 +/- 35 mg and 155 +/- 47 mg, respectively. The mean study duration was 21 +/- 8 days. Both groups improved according to HAMD (from 25.2 +/- 8.4 at baseline to 12.0 +/- 7.4 at endpoint) and CGI scores (68 % responders). Moderately severe or severe side effects occurred in 16 % of patients. Adequate dose adjustment was significantly higher in the TDM group (60 % vs. 46 %, p < 0.05); this led to a significantly higher rate of therapeutic serum levels in the TDM group (58 % vs. 44 %, p < 0.05). Direct effects of TDM were not found for effectiveness. Therapeutic TCA serum levels over weeks one to three, however, were associated with significantly better outcome at endpoint (p < 0.05) as measured with changes in the HAMD or CGI response rates from baseline to endpoint. Finally, considerable side effects occurred significantly more often when serum levels were above the therapeutic range (27 % vs. 11 %; p < 0.01). We conclude that treating depression with TCA can be optimized by early TDM, which is superior to clinical judgment on its own. Since the psychiatrists in charge were less than completely "compliant" to the recommendations provided together with serum levels, the effect could be more pronounced than this study shows. The results encourage further studies in order to optimize antidepressant pharmacotherapy when using TDM appropriately.

In-vitro data indicated a contribution of cytochrome P450 enzymes 1A2, 3A4, 2C9, 2C19 and 2D6 to biotransformation of doxepin. We studied the effects of genetic polymorphisms in CYP2D6, CYP2C9 and CYP2C19 on E- and Z-doxepin pharmacokinetics in humans. Doxepin kinetics was studied after a single oral dose of 75 mg in healthy volunteers genotyped as extensive (EM), intermediate (IM) and poor (PM) metabolizers of substrates of CYP2D6 and of CYP2C19 and as slow metabolizers with the CYP2C9 genotype *3/*3. E-, Z-doxepin and -desmethyldoxepin were quantified in plasma by HPLC. Data were analyzed by non-parametric pharmacokinetics and statistics and by population pharmacokinetic modeling considering effects of genotype on clearance and bioavailability. Mean E-doxepin clearance (95% confidence interval) was 406 (390-445), 247 (241-271), and 127 (124-139) l h(-1) in EMs, IMs and PMs of CYP2D6. In addition, EMs had about 2-fold lower bioavailability compared with PMs indicating significant contribution of CYP2D6 to E-doxepin first-pass metabolism. E-doxepin oral clearance was also significantly lower in carriers of CYP2C9*3/*3 (238 l h(-1) ). CYP2C19 was involved in Z-doxepin metabolism with 2.5-fold differences in oral clearances (73 l h(-1) in CYP2C19 PMs compared with 191 l h(-1) in EMs). The area under the curve (0-48 h) of the active metabolite -desmethyldoxepin was dependent on CYP2D6 genotype with a median of 5.28, 1.35, and 1.28 nmol l h(-1) in PMs, IMs, and EMs of CYP2D6. The genetically polymorphic enzymes exhibited highly stereoselective effects on doxepin biotransformation in humans. The CYP2D6 polymorphism had a major impact on E-doxepin pharmacokinetics and CYP2D6 PMs might be at an elevated risk for adverse drug effects when treated with common recommended doses.

Objective: Little information on the population pharmacokinetics of the tricyclic antidepressant doxepine and its pharmacologically active metabolite desmethyldoxepine is available. However, a more individualised drug therapy may be feasible if the influence of various patient characteristics on plasma concentration was known., Patients and Methods: We retrospectively analysed pharmacokinetic therapeutic drug-monitoring data in 114 psychiatric patients (79 females, 35 males) treated with doxepine for a period of 22-306 days, mostly due to major depression. The data were analysed using the computer program NONMEM. For both, doxepine and its metabolite desmethyldoxepine, a one-compartment model was chosen. Pharmacokinetic parameters clearance (CL/F) and volume of distribution (V/F) of doxepine and desmethyldoxepine were modelled in terms of both random and fixed effects., Results: The fit of the model to the concentration-time data was significantly improved when V/F was expressed as a function of weight ( P<0.05) and CL/F as a function of age ( P<0.05). Co-medication that inhibits P(450) isoenzymes lowered CL/F of doxepine by 15%., Conclusion: The analysis indicates that the factors age and, to some extent, body weight may be a guidance for individual doxepine dose regimens, which however needs confirmation in prospective clinical trials linking pharmacokinetics and therapeutic effect. Co-medication may represent only a minor important covariate.

Due to its tranquilizing properties, the tricyclic antidepressant doxepin may be misused as a doping agent in competition horses. Therefore, efficient analytical procedures are required to detect this drug in samples submitted for doping control. To screen for parent doxepin in equine blood and urine, a less specific method has been accepted employing gas chromatography (GC) combined with electron impact (EI) mass spectrometry (MS). The aim of this study was identification of doxepin metabolites providing more specific MS data to verify positives resulting from screening. Thus, after a horse was given doxepin-HCl (1 mg/kg, i.v.), blood and urine were analyzed for free or conjugated metabolites using GC combined with EI- and positive chemical ionization (PCI) MS. In both of the sample materials, cis- and trans-isomers of desmethyldoxepin were detected for up to 48 h after treatment using trifluoracetylation and GC/EI-MS. Following enzymic hydrolysis of urine and propionylation of extracts, each four isomers of hydroxy desmethyldoxepin and hydroxydoxepin were recovered for up to 24 and 48 h, respectively. These compounds were characterized by their EI- and PCI-mass spectra. Although distinct positions of the hydroxyl groups could not be determined, the presence of each two cis/trans-isomeric pairs of differently monohydroxylated metabolites may be assumed. Results reported here suggest, that screening horses for parent doxepin should be completed by analysis of its major isomeric metabolites, desmethyldoxepin and hydroxydoxepin, providing MS data specific enough for confirmatory analysis.

The tricyclic antidepressant doxepin, representing a 5:1 mixture of trans- and cis-isomers, owns tranquilizing properties. This compound has been associated with illicit medication of racing horses, and therefore should be considered in doping control. Because analysis of doxepin in equine body fluids has not been documented in the literature, a highly sensitive analytical method was developed to individually monitor the doxepin isomers in blood and urine of horses by the use of gas chromatography/mass spectrometry. Following a dose of 1 mg doxepin-HCl/kg intravenously (i.v.), both the isomers were quantified for up to 24 h in serum of horses (n=4). The beta-half-lives of the trans- and cis-isomers were 3.5 and 3.1 h, respectively. The ratio of the trans/cis-isomers was found to be constant (4.7:1) during drug elimination and thus corresponded to the original composition of the antidepressant. Up to 12 h following administration low trans-isomer concentrations in an average range of 2-6 ng/mL were detected in urine of each of the horses, while the cis-isomer was only present in two of four horses for up to 8 and 12 h, respectively. In serum, mean trans-isomer concentrations exceeded urine levels maximally 120-fold after 3 h and at least sixfold after 12 h. As serum exhibits considerably higher concentrations of the doxepin isomers as compared with urine, blood of horses is the recommended body fluid when screening for the antidepressant.

Despite the introduction of numerous new agents, tricyclic antidepressants remain an important option for the treatment of depression. Doxepin is still in wide use, and determining its concentration is a standard procedure in many psychiatric clinics. Some widely cited reviews indicate a therapeutic range from 150 to 250 ng/mL (parent plus desmethyl metabolite). The vast majority of the authors' patients fell short of these concentrations under customary doses. To resolve this issue, the authors' serum-level databank was analyzed, a questionnaire was sent to U.S. and German psychiatric university departments and laboratories, and the literature was reviewed. The main results were the following: (1) Only 9% of all samples analyzed (N = 217) displayed plasma levels (high-performance liquid chromatography) between 150 and 250 ng/mL; 88% were subtherapeutic. The mean doxepin + desmethyldoxepin steady-state serum concentration was 89+/-75 ng/mL (N = 32, doxepin >3 weeks). The mean daily dose was 143+/-30 mg. There was no correlation between concentrations and improvement. (2) A wide variety of recommendations is given by the different university departments (10-1,000 ng/mL). (3) According to the studies published to date, there is not enough evidence for recommending a therapeutic range. The preliminary suggestions given in some influential reviews have been widely adopted without critical re-evaluation. Compared with the concentrations found in the original studies, the therapeutic ranges suggested are too high. A methodologically sound study to determine a therapeutic range is required for the rational monitoring of this drug. Meanwhile, a preliminary working range of 50 to 250 ng/mL is proposed on the basis of critical reassessment of published data.

Two different oral doxepin (CAS 1668-195) formulations (Doxepin-ratiopharm 25 mg film-coated tablets as test preparation and 25 mg dragées of the reference preparation) were investigated in 30 healthy male and female volunteers in order to prove bioequivalence between these preparations. A single 75 mg oral dose (3 units of test or reference preparation) was given according to a randomised two-way cross-over design in the fasted state. Blood samples for determination of plasma concentration of doxepin and its metabolite N-desmethyldoxepin were collected at pre-defined time points up to 168 h following drug administration. A wash-out period of three weeks separated both treatment periods. Doxepin and N-desmethyldoxepin plasma concentrations were determined by means of a validated LC-MS/MS method. Values of 193,463 pgh/ml (test preparation) and 197,988 pg h/ml (reference preparation) for doxepin as well as values of 313,298 pg h/ml (test preparation) and 306,663 pgh/ml (reference preparation) for N-desmethyldoxepin for the parameter AUC0-infinity demonstrate a nearly identical extent of drug absorption. Maximum concentrations (Cmax) for doxepin/N-desmethyldoxepin of 15,960.06/6,883.69 pg/ml and 18,614.73/6,846.62 pg/ml were achieved for test and reference preparation. Time to reach doxepin maximum plasma concentration (tmax) was 1.98 h for both preparations and for N-desmethyldoxepin tmax was 4.52 h (test preparation) and 4.15 h (reference preparation). Cmax and AUC0-infinity values were tested for statistically significant differences by means of the Two One-Sided T-Tests procedure following ln-transformation of data. Bioequivalence was assumed if the 90% confidence intervals of the T/R-ratios were in the range of 80%-125% for ln-transformed AUC0-infinity and 70%-143% for ln-transformed Cmax. Based on the results obtained in this study, bioequivalence between the test and the reference preparation was demonstrated.

A sensitive method for the simultaneous determination of doxepin and its active metabolite desmethyldoxepin in plasma was established, using high-performance liquid chromatographic separation with tandem mass spectrometric detection. The samples were extracted with hexane-isoamyl alcohol, separated on a Phenomenex Luna C18 5 microm, 150x2.1 mm column with a mobile phase consisting of methanol-water-formic acid (600:400:0.5, v/v) at a flow-rate of 0.25 ml/min. Detection was achieved by a Perkin-Elmer API 2000 mass spectrometer at unit resolution in multiple reaction monitoring mode monitoring the transition of the protonated molecular ions m/z 280.2, 266.2 and 250.1 to the product ions m/z 107.1, 107.1 and 191.0 for analyte, metabolite and internal standard (benzoctamine-HCl), respectively. TurbolonSpray ionisation was used for ion production. The mean recovery for doxepin and desmethyldoxepin was 90% and 75%, respectively, with a lower limit of quantification at 0.320 ng/ml and 0.178 ng/ml for the analyte and its metabolite, respectively, using 0.5 ml plasma for extraction. This is the first assay method described for the simultaneous determination of doxepin and desmethyldoxepin in plasma using LC-MS-MS. The method is sensitive enough to be used in drug bioavailability studies with doxepin.

Fluoxetine, imipramine, doxepine and opipramol after liquid-liquid extraction were separated by TLC on silica gel 60 GF254 by ascending and horizontal technique using suitable mobile phases. The substances were identified by UV irradiation at 254 nm and by spraying of Amelinka's reagnet (up to the amount 0.25 microgram fluoxetine and 0.05 microgram imipramine, doxepine and opipramol).

It has been shown that a single pulse-dosing (PD) dose of clomipramine improves depressive symptoms. However, so far PD and conventional (CONV) application of antidepressants have never been directly compared for an extended period. We performed a double-blind study of PD and CONV application of doxepin (DOX) in depressed patients. After a 1-week placebo treatment, nine parents in the PD group received 250 mg of DOX every 6 days and placebo on the other days until day 39. Ten patients in the CONV group received increasing dosages of DOX until day 7 and 250 mg DOX on the other days for 39 days. Three dexamethasone (DEX)-suppression/corticotropin-releasing hormone (CRH)-stimulation tests were completed: (1)during the initial placebo period; (2)on day 9; and (3)on day 21. In the PD group, scores on the Hamilton Rating Scale for Depression (HAM-D) differed from baseline only after day 36 (17.1 +/- 7.0 vs. 22.7 +/- 2.8, p < 0.03). In the CONV group, however, HAM-D scores improved significantly after 2 days (22.8 +/- 7.2 vs. 26.5 +/- 5.7, p < 0.02) and continued to improve until day 39 (7.3 +/- 5.8). From day 25 to 39, there were significant differences between the HAM-D scores of the two groups. In the PD group, the decline of cortisol after DEX pretreatment was nonsignificant (NS) at both follow-up test occasions (35.9 +/- 40.7 vs. 24.0 +/- 20.7 vs. 23.6 +/- 26.6 micrograms/mL). In the CONV group, a significant decrease was observed at the second test (61.8 +/- 61.9 vs. 10.7 +/- 4.2 vs. 19.8 +/- 19 micrograms/mL, p < 0.05, respectively, NS). The area-under-the-curve cortisol response after CRH was attenuated in the PD group (5,667 +/- 2,910 vs. 1,883 +/- 2,178 vs. 2,239 +/- 2,583 [arbitrary unit], p < 0.01, respectively, p < 0.01) and in the CONV group (5,710 +/- 4,734 vs. 1,267 +/- 2,053 vs. 445 +/- 1,016 [arbitrary unit], NS, respectively, p < 0.02. We conclude that CONV application of DOX is clinically superior compared with PD and that both modes of application have attenuating effects on hypothalamus-pituitary-adrenal system activity.

Little information exists on the concentrations of antidepressants and their metabolites in CSF. We measured plasma and CSF levels of trans-doxepin (trans-DOX) and DOX metabolites in 12 depressed patients treated with DOX (250 mg/day) for 6 days. Spinal taps and blood samples were taken on day 7, 10 h after drug administration. Trans-DOX, cis-desmethyldoxepin (cis-DM-DOX), trans-desmethyldoxepin (trans-DM-DOX) and di-desmethyldoxepin (DDM-DOX) were analyzed in CSF and plasma samples by HPLC with column-switching. Although DOX was given as a mixture of 85% trans-DOX and 15% of the pharmacologically more active cis-DOX, we found similar amounts of cis-DM-DOX and trans-DM-DOX in plasma (59.8 +/- 45.1 versus 72.0 +/- 60.0 ng/ml; NS), suggesting that isomerization of DOX had taken place. Trans-DOX and DOX metabolites could be detected in CSF of most patients. Relatively low CSF concentrations of the active metabolite cis-DM-DOX were measured. Clinical efficacy, as assessed by HAMD scores, was not significantly related to plasma or CSF concentrations of trans-DOX or its metabolites. Trans-DOX and DOX metabolites were distributed differently between plasma and CSF. It is concluded that isomerization of DOX is not only relevant for neuronal uptake inhibition, but also for the transport of the metabolites.

Doxepin is a tricyclic antidepressant marketed as an irrational mixture of cis- and trans-geometric isomers in the ratio of 15:85. A convenient high-performance liquid chromatographic (HPLC) procedure for simultaneous quantitation of geometric isomers of doxepin and N-desmethyldoxepin in plasma and urine is described. The HPLC procedure employed a normal phase system with a silica column and a mobile phase consisting of hexane-methanol-nonylamine (95:5:0.3, v/v/v), a UV detector and nortriptyline as the internal standard. The liquid-liquid extraction solvent was a mixture of n-pentane-isopropanol (95:5, v/v). The limit of quantitation was 1 ng/ml for each isomer. The calibration curves were linear over the ranges 1-200 ng/ml (plasma) and 1-400 ng/ml (urine). In plasma, the accuracy (mean +/- S.D.) (97.53 +/- 1.67%) and precision (3.89 +/- 1.65%) data for trans-doxepin were similar to corresponding values for urine, i.e., 97.10 +/- 2.40 and 3.82 +/- 1.14%. Accuracy and precision data for trans-N-desmethyldoxepin in plasma were 97.57 +/- 2.06 and 4.38 +/- 3.24%, and in urine were 97.64 +/- 3.32 and 5.26 +/- 1.83%, respectively. Stability tests under three different conditions of storage indicated no evidence of degradation. The recovery of doxepin was 61-64% from plasma and 63-68% from urine. The method has been applied to analyses of plasma and urine samples from human volunteers and animals dosed with doxepin.

In the treatment of depressive disorders the onset of action can be accelerated if the antidepressant drug is initially administered by intravenous infusion. It is not clear whether this effect is due to pharmacological or to psychological effects of the infusion setting. The necessary switch to oral administration may be problematic. Uncontrolled observations indicate that it could be associated with a remarkable deterioration in the course of the disease. This randomized double-blind placebo-controlled study on doxepin is the first investigation of the effect of the switch from parenteral to oral administration on symptoms of endogenous depression. The hypothesis to be tested, that there is a significant worsening of treatment response during the switch, must be rejected on the basis of objective and subjective psychometric tests. There was in fact a continuous improvement. Precondition was a selection of patients with typical "endogenous" depressions and maintenance of at least constant plasma levels of the active antidepressants. In patients under the age of 65 years this can generally be achieved by switching in a ratio of 125 mg i.v. to 250 per os in the case of doxepin. Individual case studies indicated that a worsening in the patient's progress after switching was correlated with a decreasing plasma level of the active drug. Low plasma level already during the infusion period, insufficient response, and questionable compliance on oral medication were associated. Due to large interindividual differences of plasma levels by a factor of 10, measurements before and after switching are required.

A reversed-phase HPLC method for determination of phenothiazines and tricyclin antidepressants in whole blood was described. In this paper, a model 1090 HPLC with DAD and a zorbax ODS column was used. The mobile phase was methanol: water: tritely amine (75:24.7:0.3) with pH 7.5. Cyproheptadine was used as internal standard in this method. Blood samples were extracted with the solid-phase extraction method and the liquid-liquid method. This method is suitable in forensic toxicology analysis for basic drugs.

Nonresponse to tricyclic antidepressant (TCA) treatment is observed in about one-third of depressed patients. The cause(s) for nonresponse - apart from disease-specific effects - might be the failure to build up sufficiently high serum TCA levels due to noncompliance, substance abuse, rapid metabolism, or low dose. We carried out a retrospective analysis relating antidepressant serum levels to patient data obtained in the naturalistic setting of the Psychiatric Hospital of the Bonn University during the introductory phase of drug-monitoring. Case reports of 110 depressed inpatients who were treated with amitriptyline or doxepin were analyzed with respect to the following: medication and comedication, daily dose, type and duration of treatment, serum TCA concentrations (analyzed by the fluorescence polarization immunoassay), age, sex, body weight, abuse of nicotine or alcohol intake, serum transaminases (ALT, alanine aminotransferase, and AST, aspartate amino transferase), gamma-glutamyltranspeptidase (gamma-GT) and creatinine, compliance, and response. The salient findings were: 1. Serum TCA concentrations increased linearly with the daily amitriptyline dose but not with that of doxepin. 2. Interindividually, there was an eight to ten-fold difference in serum TCA concentrations at steady-state with 150 mg/day of either drug; longitudinally, we observed intraindividually a coefficient of variation of 8% and 12% for amitriptyline and doxepin respectively. 3. With amitriptyline (150 mg/day), the correlation between age and serum TCA concentrations was low (r = 0.33, p < 0.055) and no correlation was found after the administration of doxepin (150 mg/day), nor was there any correlation between age and dose-adjusted serum TCA concentrations after the administration of either drug. 4. Nonresponders had significantly lower serum levels than responders. These results suggest that patients should not qualify as nonresponders unless it can be demonstrated (and it is clinically applicable) that the steady-state serum TCA levels are stable within the upper limit of the recommended therapeutic range and serum level.

Carbon-11 labeled metabolites in human plasma were analyzed by high-performance liquid chromatography during positron emission tomography (PET) studies using the dopamine D2 ligand [11C]YM-09151-2 as well as the histamine H1 ligands [11C]doxepin and [11C]pyrilamine. For all the three tracers, blood clearance of the radioactivity was extremely rapid after an i.v. injection. The plasma protein-binding of [11C]YM-09151-2 and [11C]doxepin had protective effects upon the metabolic alteration of the ligands, whereas [11C]pyrilamine was free from the protein-binding and immediately degraded. The degradation of [11C]doxepin was more rapid in epileptic patients on medication than in normal subjects. These results indicate that analysis of metabolites in the plasma is necessary to determine the accurate arterial input function for quantitative PET measurement.

A high-performance liquid chromatographic (HPLC) method was developed for the quantitative, simultaneous determination of the following four compounds in serum: E-doxepin, Z-doxepin, E-desmethyldoxepin, and Z-desmethyldoxepin. A 3-microns analytical silica column (6 x 100 mm) was employed with the mobile phase 0.025 M phosphate:acetonitrile:n-nonylamine (80:20:1). This HPLC method allows for the accurate measurement of all four isomeric compounds.

A flow through dissolution system was applied to obtain biorelevant dissolution rates from controlled release systems for parenteral administration using the antidepressant doxepin as a model compound. Plasma concentrations were simulated using the disposition function of doxepin obtained from administration of an aqueous doxepin solution (AponalR) to beagle dogs. Input functions were obtained from in vitro dissolution experiments with three parenteral controlled release suspensions of doxepin hydrochloride (DHCl), doxepin pamoate (DP-1), and microspheres of doxepin hydrochloride in poly D,L-lactid-co-glycolid (MC-1) in isopropyl myristate. The predicted plasma concentrations were compared with experimentally obtained concentrations in vivo. Good correlations (r > 0.88) between observed and predicted data were obtained for all formulations investigated. Similarly, in vivo release kinetics calculated by the Loo-Riegelman method were compard with release kinetics measured in vitro and showed good correlations (r > 0.89). It is anticipated that the in vitro dissolution system permits assessment of the clinical relevance of observed variations in dissolution rates e.g. between batches of one formulation.

A sensitive method suitable for the determination of tricyclic and other antidepressants in postmortem and clinical specimens is presented. The procedure, which utilizes reversed-phase HPLC combined with dual ultraviolet wavelength detection, enables the separation of 17 commonly prescribed antidepressants and some selected metabolites in a single extraction. Peak purity was confirmed using absorbance ratios at 220 nm and 254 nm wavelengths and revealed little interference from other eluting analytes. The blood detection limit for most antidepressants was 50 ng/ml. The most commonly observed antidepressants in 281 forensic cases analysed over a two-year period with the described method were dothiepin, amitriptyline, nortriptyline and doxepin.

Parenteral slow release formulations of doxepin in lipid vehicles were prepared in the form of suspensions of doxepin hydrochloride, doxepin pamoate and of poly D,L-lactid and poly D,L-lactid-co-glycolide microspheres containing doxepin hydrochloride. The drug particles or the drug containing microspheres were suspended in the vehicles isopropylmyristate or Miglyol. The dissolution rate of the different doxepin formulations was investigated in two flow through cells, a membrane and a non-membrane system, using either plain buffer or human plasma containing buffer as dissolution media, in order to study the influence of dissolution conditions on dissolution rates. An attempt was made to obtain biorelevant dissolution data. In the membrane system a linear relationship between time and percent drug dissolved during the period of investigation was found. Drug release was very slow and incomplete, especially when buffer was used as dissolution medium. Dissolution data from the nonmembrane system were fitted to monoexponential and biexponential models, respectively. Significant differences were found using different modes of formulation positioning and using the two dissolution media. The most rapid release rates were found when the formulations were spread on glass carriers and plasma was used as dissolution medium. It is suggested that this dissolution procedure has physiological relevance.

Commercial preparations of the tricyclic anti-depressant doxepin contain 15% of the more active cis-doxepin and 85% of the trans-isomer. The single dose pharmacokinetics of doxepin and its major metabolite N-desmethyldoxepin were examined in 30 healthy young men. Results for total doxepin showed wide intersubject variation in all pharmacokinetic parameters except tmax and Cmax. Plasma levels of cis-doxepin were extremely low and it was only possible to estimate the stereoselective pharmacokinetics of the parent drug in 3 subjects. The data from those particular subjects resulted in an average ratio of cis- to trans-doxepin isomers in plasma of 15:85. In contrast, the mean plasma levels of cis-N-desmethyldoxepin in 28 subjects exceeded those of the trans-isomer at every time point after 10 h, such that the areas under the plasma concentration versus time curves (AUC) of cis-N-desmethyldoxepin were significantly higher than those of the corresponding trans-isomer. This phenomenon may play an important role in the therapeutic action of doxepin since it has been suggested that cis-N-desmethyldoxepin is pharmacologically active. In 2 subjects, however, the AUC0-inf of trans-N-desmethyldoxepin were respectively 4 and 8 fold higher than those of the cis-isomer.

We have investigated the predictive value of single dose levels for steady state levels of two commonly used antidepressants, doxepin (DOX) and imipramine (IMI) in a population of 40 outpatients with unipolar depression. After a wash-out period, patients were given 75 mg of either doxepin or imipramine and blood samples were drawn 16 h after the dose. Treatment was continued for 2 weeks on a fixed 100 mg/day dose and after that the dose was adjusted according to patients' response. Drugs and their demethylated metabolites were determined weekly using a GC technique. There was a large (more than 5-fold) inter-individual variation in both the single dose and steady-state levels of the two drugs. However, a significant correlation was found between the single-dose levels and initial steady-state levels for both. The respective linear regression equations were: DOX (parent drug & demethylated metabolite): y = 1.4x + 16.8; r = 0.75, p less than 0.001; IMI (parent drug & demethylated metabolite): y = 3.1x + 4.9; r = 0.85; p less than 0.001. These results confirm, in a population of depressed outpatients, previous findings of a significant correlation between single dose and steady state plasma levels of imipramine, and indicate for the first time that such a correlation also exists for another commonly used tricyclic antidepressant, doxepin. From this relationship, dose requirement can be estimated for individual patients to achieve a desired steady-state concentration of total tricyclics (parent drug & metabolite).

Plasma levels of doxepin and desmethyldoxepin were measured in split samples of 20 depressed patients treated with doxepin by using a conventional extraction and gas chromatography method on a packed column (method 1) and derivation of secondary amine and gas chromatography on a capillary column, allowing the separation and simultaneous quantitation of the cis- and trans-isomers of the two compounds (method 2). We have found that significantly higher levels of desmethyldoxepin and of total drug are detected in plasma when the two isomers are separated and measured by method 2. We concluded that the plasma levels of doxepin reported in most previous studies were underestimated since the cis- and trans-isomers were not separated and included in the total drug concentration. Because the activity of the two isomers is different and their proportion varies in individual patients, we suggest that in future studies correlating plasma levels and the clinical effects of doxepin, both the cis- and the trans-isomers of doxepin and desmethyldoxepin be determined.

An influence of several adsorbents and the composition of the eluent mixtures on the separation of dibenzoazepine and dibenzocycloheptadiene derivatives was examined by thin-layer chromatography. The best system (RP-18 and methanol-buffer solution pH 8.5 19:1) was employed for the separation of amitryptiline and doxepine by HPLC. Both compounds were determined in ng amounts in pharmaceutical preparations and in blood by addition and in patients blood. Doxepine was used as internal standard for the determination of amitryptiline.

A case is described of ventricular arrhythmias associated with doxepin and amitriptyline treatment in a patient with preexisting heart disease. A significant correlation was found between the occurrence of premature ventricular depolarizations and serum levels of both antidepressants.