RESUMEN
Doxepin, a Class-I Biopharmaceutics Drug Disposition Classification System (BDDCS) drug, exhibits poor bioavailability due to extensive first-pass metabolism. This research focuses on enhancing the delivery of doxepin by formulating nanostructured lipid carriers (NLCs) through the utilization of the Box-Behnken Design methodology. These optimized NLCs are intended for intranasal administration, with the ultimate goal of improving nose-to-brain drug delivery. NLCs were formulated using a high-speed homogenization technique. The optimized batch had a small particle size (75.80 ± 5.48 nm, PDI = 0.286), high entrapment efficiency (94.10 ± 0.16%), and sustained ex vivo release (82.25 ± 4.61% at 24 h). Characterization studies confirmed the conversion of doxepin from a crystalline to an amorphous state with uniform distribution in the lipid matrix. In vivo pharmacokinetic studies in rats showed significantly higher doxepin concentration in the brain tissue (Cmax = 16.77 µg/g, tmax = 30 min) after intranasal administration compared to intravenous administration (Cmax = 2.53 µg/g, tmax = 6 h). High-drug targeting efficiency (DTE = 284.3%) and direct transport percentage (DTP = 64.8%) suggested direct penetration of NLCs in the brain via olfactory and trigeminal pathways. In conclusion, the study highlights the potential of NLCs to improve the bioavailability of doxepin through nose-to-brain delivery and thereby potentially enable the treatment of neurological disorders.
Asunto(s)
Administración Intranasal , Disponibilidad Biológica , Encéfalo , Doxepina , Portadores de Fármacos , Lípidos , Nanoestructuras , Animales , Doxepina/farmacocinética , Doxepina/administración & dosificación , Encéfalo/metabolismo , Lípidos/química , Portadores de Fármacos/química , Ratas , Masculino , Nanoestructuras/química , Tamaño de la Partícula , Sistemas de Liberación de Medicamentos/métodos , Ratas Sprague-Dawley , Liberación de Fármacos , Biofarmacia/métodos , Mucosa Nasal/metabolismoRESUMEN
Receptor occupancy is an indicator of antipsychotic efficacy and safety. It is desirable to simultaneously determine the occupancy of multiple brain receptors as an indicator of the efficacy and central side effects of antipsychotics because many of these drugs have binding affinities for various receptors, such as dopamine 2 (D2), histamine 1 (H1), and muscarinic acetylcholine (mACh) receptors. The purpose of this study was to develop a method for the simultaneous measurement of multiple receptor occupancies in the brain by the simultaneous quantification of unlabeled tracer levels using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Rats were pre-administered with a vehicle, displacer, or olanzapine, and mixed solutions of raclopride, doxepin, and 3-quinuclidinyl benzilate (3-QNB) were administered (3, 10, and 30 µg/kg). The brain tissue and plasma tracer concentrations were quantified 45 min later using LC-MS/MS, and the binding potential was calculated. The highest binding potential was observed at 3 µg/kg raclopride, 10 µg/kg doxepin, and 30 µg/kg 3-QNB. Tracer-specific binding at these optimal tracer doses in the cerebral cortex was markedly reduced by pre-administration of displacers. D2, H1, and mACh receptor occupancy by olanzapine increased in a dose-dependent manner, reaching 70-95%, 19-43%, and 12-45%, respectively, at an olanzapine dose range of 3-10 mg/kg. These results suggest that simultaneous determination of in vivo D2, H1, and mACh receptor occupancy is possible using LC-MS/MS.
Asunto(s)
Antipsicóticos , Olanzapina , Ratas Sprague-Dawley , Receptores de Dopamina D2 , Receptores Histamínicos H1 , Receptores Muscarínicos , Espectrometría de Masas en Tándem , Animales , Espectrometría de Masas en Tándem/métodos , Ratas , Masculino , Antipsicóticos/administración & dosificación , Cromatografía Liquida/métodos , Receptores de Dopamina D2/metabolismo , Receptores Muscarínicos/metabolismo , Receptores Muscarínicos/efectos de los fármacos , Receptores Histamínicos H1/metabolismo , Olanzapina/farmacocinética , Olanzapina/administración & dosificación , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Benzodiazepinas/análisis , Benzodiazepinas/metabolismo , Benzodiazepinas/farmacocinética , Racloprida/metabolismo , Doxepina/farmacocinética , Quinuclidinil Bencilato/metabolismo , Relación Dosis-Respuesta a DrogaRESUMEN
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, V0 (n = 905), a group of patients co-medicated with doxepin, VDOX (n = 25) and a second group, co-medicated with mirtazapine, VMIR, 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.
Asunto(s)
Antidepresivos de Segunda Generación/sangre , Ciclohexanoles/sangre , Succinato de Desvenlafaxina/sangre , Doxepina/sangre , Mianserina/análogos & derivados , Clorhidrato de Venlafaxina/sangre , Adulto , Antidepresivos de Segunda Generación/farmacocinética , Antidepresivos de Segunda Generación/uso terapéutico , Ciclohexanoles/farmacocinética , Ciclohexanoles/uso terapéutico , Bases de Datos Factuales , Succinato de Desvenlafaxina/farmacocinética , Succinato de Desvenlafaxina/uso terapéutico , Doxepina/farmacocinética , Doxepina/uso terapéutico , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Humanos , Masculino , Mianserina/sangre , Mianserina/farmacocinética , Mianserina/uso terapéutico , Persona de Mediana Edad , Mirtazapina , Polifarmacia , Clorhidrato de Venlafaxina/farmacocinética , Clorhidrato de Venlafaxina/uso terapéuticoRESUMEN
AIM: Doxepin is a traditional tricyclic antidepressant with analgesic and anesthetic properties when applied topically to the mucosa. Doxepin is one approach in treating insomnia and depression in Parkinson's disease. Patients with Parkinson's disease suffer difficulties in swallowing. Therefore, it was the aim of this study to develop a buccal-adhesive delivery system. METHODS: Pectin was modified with cysteine. Stability assays in form of disintegration assay according to the Ph.Eur were performed. Furthermore, bioadhesiveness on buccal mucosa was investigated incorporating the drug doxepin. RESULTS: The adhesiveness was improved 1.4-fold and revealed a sustained release over 3 h. CONCLUSION: Taking these findings into account, the modifications render this designed excipient fruitful for buccal delivery.
Asunto(s)
Cisteína/química , Doxepina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/química , Pectinas/química , Adhesividad , Administración Bucal , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Doxepina/efectos adversos , Doxepina/farmacocinética , Liberación de Fármacos , Estabilidad de Medicamentos , Humanos , Mucosa Bucal/efectos de los fármacosRESUMEN
Due to the lack of certified reference material, a reliable quantification in complex postmortem matrices can only be performed either by the addition of isotope-labelled standards or by the standard addition method. Although standard addition is a basic quantification procedure, its practical implementation is challenging, and a highly reproducible extraction method is essential. Therefore, an automated solid-phase extraction screening procedure was validated in respect to the specific requirements in postmortem analyses, using pig brain fortified with nine compounds to represent a realistic postmortem setting. The validation parameters linearity, repeatability, reproducibility and recovery were selected to test the method's 'fitness for purpose'. All obtained results were satisfying, although the method was not optimized for the selected compounds. Therefore, this validated method could be used for further standard addition experiments to evaluate the importance of the initial estimated concentration for the calculation of concentrations to set up the calibration curve. We could show that the best results were obtained when the estimated concentration was close to the real concentration. In case of a deviation, an underestimation is more favorable than an overestimation.
Asunto(s)
Encéfalo/metabolismo , Preparaciones Farmacéuticas/análisis , Animales , Calibración , Cocaína/análogos & derivados , Cocaína/farmacocinética , Codeína/farmacocinética , Diazepam/farmacocinética , Doxepina/farmacocinética , Ibuprofeno/farmacocinética , Metadona/farmacocinética , Morfina/farmacocinética , Fenobarbital/farmacocinética , Reproducibilidad de los Resultados , Extracción en Fase Sólida , PorcinosRESUMEN
According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 µg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 µg/cm(2)/µg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.
Asunto(s)
Analgésicos/administración & dosificación , Doxepina/administración & dosificación , Mucosa Bucal/efectos de los fármacos , Absorción por la Mucosa Oral , Administración Bucal , Analgésicos/farmacocinética , Analgésicos/toxicidad , Animales , Doxepina/farmacocinética , Doxepina/toxicidad , Femenino , Técnicas In Vitro , Mucosa Bucal/metabolismo , Mucosa Bucal/patología , Absorción por la Mucosa Oral/efectos de los fármacos , Permeabilidad , Valor Predictivo de las Pruebas , Porcinos , Distribución TisularRESUMEN
Thermoreversible biogels can serve as effective systems for delivery of drugs through nose with increased nasal residence time. The objective of this study was to use chitosan and glycerophosphate based thermoreversible systems for delivery of doxepin to brain through intranasal administration. Formulations were prepared by admixture of suitable dilutions of chitosan and glycerophosphate with or without polyethylene glycol, followed by addition of the antidepressant doxepin hydrochloride. Both systems were evaluated for gelling characteristics, rheology, mucoadhesion, in vitro release, and ex vivo permeation through sheep nasal mucosa. In vivo efficacy was evaluated in Swiss albino mice through the forced swim test. Nasal tissues of mice subjected to repeated exposure to formulation were evaluated histopathologically. Both formulations gelled rapidly at 37°C, returned to sol state on cooling, and exhibited thixotropy. Addition of polyethylene glycol decreased the glycerophosphate content required for gelation and rendered the formulation isotonic. Both gels showed good mucoadhesion, enhanced drug permeation, and provided prolonged in vitro release at 37°C. Efficacy of the formulation in treated groups was inferred from the measured pharmacodynamic parameter and histopathological reports of formulation treated groups showed no significant local toxicity. The biogels could be potential systems for effective drug delivery to brain via nose.
Asunto(s)
Antidepresivos Tricíclicos , Encéfalo/metabolismo , Doxepina , Sistemas de Liberación de Medicamentos , Absorción Nasal , Cavidad Nasal/metabolismo , Administración Intranasal , Animales , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/farmacología , Quitosano/química , Quitosano/farmacocinética , Quitosano/farmacología , Doxepina/farmacocinética , Doxepina/farmacología , Geles , Glicerofosfatos/química , Glicerofosfatos/farmacocinética , Glicerofosfatos/farmacología , Ratones , Ranidae , OvinosRESUMEN
Valproic acid and the antidepressants doxepin and venlafaxine are frequently used psychotropic drugs. In the literature, an influence of valproic acid on serum levels of antidepressants has been described, although studies have focused on amitriptyline. The authors assessed their therapeutic drug monitoring (TDM) database for patients receiving a combination of doxepin or venlafaxine and valproic acid and compared these samples with matched controls without valproic acid comedication in terms of the serum concentration of antidepressants. The mean dose-corrected serum concentration of doxepin+N-doxepin in 16 patients who received valproic acid comedication was higher (2.171±1.482 ng/ml/mg) than that in the matched controls (0.971±0.857 ng/ml/mg, P<0.003). We also found a significant correlation between valproic acid serum level and dose-corrected doxepin+N-doxepin serum level (Spearman's ρ r=0.602, P<0.014). The mean dose-corrected serum level of venlafaxine+O-desmethylvenlafaxine in 41 patients who received valproic acid comedication did not differ significantly from that of the matched controls (P<0.089), but there was a significant difference between both groups in the dose-corrected serum level of O-desmethylvenlafaxine (1.403±0.665 vs. 1.102±0.444, P<0.017). As a consequence, if a combination of valproic acid with doxepin or venlafaxine is administered, cautious dosing is advisable and TDM should be performed.
Asunto(s)
Antidepresivos/uso terapéutico , Ciclohexanoles/uso terapéutico , Depresión/tratamiento farmacológico , Doxepina/uso terapéutico , Monitoreo de Drogas , Ácido Valproico/uso terapéutico , Adulto , Anciano , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Biotransformación/efectos de los fármacos , Ciclohexanoles/administración & dosificación , Ciclohexanoles/efectos adversos , Ciclohexanoles/farmacocinética , Depresión/sangre , Relación Dosis-Respuesta a Droga , Doxepina/administración & dosificación , Doxepina/efectos adversos , Doxepina/farmacocinética , Interacciones Farmacológicas , Quimioterapia Combinada/efectos adversos , Femenino , GABAérgicos/administración & dosificación , GABAérgicos/efectos adversos , GABAérgicos/farmacocinética , GABAérgicos/uso terapéutico , Alemania , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/efectos adversos , Antagonistas de los Receptores Histamínicos/farmacocinética , Antagonistas de los Receptores Histamínicos/uso terapéutico , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , Ácido Valproico/farmacocinética , Clorhidrato de VenlafaxinaRESUMEN
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.
Asunto(s)
Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/envenenamiento , Doxepina/farmacocinética , Doxepina/envenenamiento , Antidepresivos Tricíclicos/sangre , Hidrocarburo de Aril Hidroxilasas/genética , Cromatografía Liquida , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP2D6/genética , Doxepina/sangre , Interacciones Farmacológicas , Femenino , Toxicología Forense , Genotipo , Hospitales Psiquiátricos , Humanos , Persona de Mediana Edad , Mutación , Farmacogenética , Suicidio , Espectrometría de Masas en TándemRESUMEN
When liquid donors/receivers are used for in vitro skin permeation studies, excess hydration can change skin properties compared to in vivo conditions. A novel in vitro method of determining the permeability of drugs through skin was developed that avoids exposing the membrane to dilute donor/receiver solutions. The drug is dissolved in an unstirred donor gel, and diffuses through a membrane into an unstirred gel receiver that can potentially be adjusted to mimic physiological conditions. Pulsatile microdialysis (PMD) was used to sample local concentrations in the receiver medium, and a model was developed to allow the determination of permeability. For Doxepin HCl, permeabilities through artificial membranes and human cadaver skin were determined using the new and previously reported methods. For artificial membranes that minimally hydrate, the new method gave consistent but slightly lower permeability values. For human cadaver skin, the permeability determined using the new method was 1/6 that of the fully hydrated skin. Limitations of the model, their relations to experimental design and data analysis were evaluated. It was concluded that this method can be applied to characterize membrane permeabilities using experiments that may avoid membrane breakdown and more closely mimic physiological conditions.
Asunto(s)
Doxepina/farmacocinética , Microdiálisis/métodos , Modelos Teóricos , Absorción Cutánea , Cámaras de Difusión de Cultivos , Doxepina/administración & dosificación , Humanos , Masculino , Membranas Artificiales , Modelos Biológicos , Permeabilidad , Piel/metabolismoRESUMEN
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.
Asunto(s)
Trastorno Depresivo/tratamiento farmacológico , Doxepina/sangre , Doxepina/líquido cefalorraquídeo , Adulto , Anciano , Antidepresivos Tricíclicos/sangre , Antidepresivos Tricíclicos/líquido cefalorraquídeo , Antidepresivos Tricíclicos/farmacocinética , Trastorno Depresivo/sangre , Trastorno Depresivo/líquido cefalorraquídeo , Doxepina/análogos & derivados , Doxepina/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Doxepin binds with high specificity and affinity to the histamine H(1) receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H(1) receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.
Asunto(s)
Doxepina/administración & dosificación , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Adulto , Antidepresivos Tricíclicos/efectos adversos , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/uso terapéutico , Ensayos Clínicos como Asunto , Doxepina/efectos adversos , Doxepina/farmacocinética , Doxepina/farmacología , Femenino , Humanos , MasculinoRESUMEN
The electroporation mediated transdermal delivery (Protocol - 120 V, 10 ms, 30 pulses at 1 Hz with post pulse waiting period of 20 min) of doxepin using pure drug solution (PDS) and doxepin-hydroxypropyl-beta-cyclodextrin (HPCD) complex solution (CDS) was studied using porcine epidermis model. The stoichiometry of drug-HPCD inclusion complex was determined by differential scanning calorimetry (DSC). The amount of doxepin retained in the epidermis following electroporation did not differ significantly between PDS and CDS. When the drug loaded epidermis was subjected to "Release studies", doxepin release attained a plateau within approximately 2.5 days in case of PDS, whereas in case of CDS, doxepin release was prolonged up to 5 days. Mechanistic studies across the nonbiological barriers demonstrated that the slow dissociation of complex was responsible for sustained release of drug from the epidermis. Pharmacodynamic studies were carried out by electroporation mediated delivery of CDS and PDS in hairless rats. The analgesic effect of doxepin was prolonged in case of CDS as compared to PDS.
Asunto(s)
Antidepresivos Tricíclicos/administración & dosificación , Doxepina/administración & dosificación , Portadores de Fármacos/química , Neuralgia Posherpética/tratamiento farmacológico , Absorción Cutánea/efectos de los fármacos , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina , Administración Cutánea , Animales , Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/uso terapéutico , Preparaciones de Acción Retardada , Doxepina/farmacocinética , Doxepina/uso terapéutico , Electroporación , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Técnicas In Vitro , Membranas Artificiales , Neuralgia Posherpética/metabolismo , Permeabilidad , Ratas , Ratas sin Pelo , PorcinosRESUMEN
BACKGROUND: Doxepin is a tricyclic compound that has been used extensively for the treatment of depressive and anxiety disorders for approximately thirty years. It was noted early to have sedative effects and assist with the improvement of disrupted sleep patterns, but in higher antidepressant doses it was also noted to have significant anticholinergic and antinoradrenergic properties. These properties led to significant dose-limiting side effects, which at times precluded its effective use. Recently, doxepin has seen renewed interest in low doses as an H1 specific antagonist in sleep disorders. OBJECTIVE: The review seeks systematically to examine currently published data on the use of doxepin for the treatment of insomnia, and its pharmacological basis. METHODS: Medline articles showing from a search of 'doxepin and insomnia' were included in the review. RESULTS/CONCLUSION: Currently available data support the use of low-dose doxepin as preferential H1 antagonist for the treatment of primary insomnia. There are likely preferential effects upon sleep maintenance insomnia compared with sleep initiation given the role of histamine in the sleep-wake cycle.
Asunto(s)
Antidepresivos Tricíclicos/farmacocinética , Antidepresivos Tricíclicos/uso terapéutico , Relación Dosis-Respuesta a Droga , Doxepina/farmacocinética , Doxepina/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Antidepresivos Tricíclicos/administración & dosificación , Química Farmacéutica , Doxepina/administración & dosificación , Doxepina/química , Esquema de Medicación , Humanos , Hipnóticos y Sedantes/farmacología , Polisomnografía , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Sueño/efectos de los fármacos , Sueño/fisiología , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismo , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Resultado del Tratamiento , VigiliaRESUMEN
BACKGROUND: The central histaminergic neuron system modulates various brain functions, including eating behavior. We hypothesized that women have higher density of histamine H1 receptor (H1R) in the limbic system than men and that the density of central H1R is increased in patients with anorexia nervosa (AN). METHODS: Subjects were 12 female AN patients, 12 healthy female subjects, and 11 healthy male subjects. Positron emission tomography with H1R radioligand [(11)C]doxepin was performed on all subjects and regions of interest based analysis was conducted to evaluate brain H1R binding potential (BP). Abnormal eating behavior, depression, and anxiety of subjects were evaluated using the Eating Attitude Test-26 (EAT-26), Self-Rating Depression Scale (SDS), and State-Trait Anxiety Inventory (STAI), respectively. RESULTS: Binding potential of [(11)C]doxepin in female subjects was significantly higher than that in male subjects at the following brain sites: amygdala, hippocampus, medial prefrontal cortex, orbitofrontal cortex, and temporal cortex. Anorexia nervosa patients showed significantly higher BP of [(11)C]doxepin in the amygdala and lentiform nucleus than the control female subjects. In AN patients, BP of [(11)C]doxepin in the amygdala and thalamus negatively correlated with EAT-26 scores. There was a significant negative correlation between BP of [(11)C]doxepin and SDS or STAI scores in the amygdala, anterior cingulate cortex, and orbitofrontal cortex of AN patients. CONCLUSIONS: These findings support the hypothesis that women have higher H1R density in the limbic system than men and suggest that AN patients may have higher expression of H1R in the limbic brain, particularly in the amygdala.
Asunto(s)
Anorexia Nerviosa/metabolismo , Química Encefálica/fisiología , Receptores Histamínicos H1/fisiología , Anorexia Nerviosa/diagnóstico por imagen , Anorexia Nerviosa/psicología , Antidepresivos Tricíclicos/farmacocinética , Ansiedad/psicología , Encéfalo/patología , Interpretación Estadística de Datos , Doxepina/farmacocinética , Conducta Alimentaria/efectos de los fármacos , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Sistema Límbico/diagnóstico por imagen , Sistema Límbico/metabolismo , Masculino , Tomografía de Emisión de Positrones , Escalas de Valoración Psiquiátrica , Caracteres Sexuales , Adulto JovenRESUMEN
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.
Asunto(s)
Antidepresivos Tricíclicos/envenenamiento , Citocromo P-450 CYP2D6/deficiencia , Citocromo P-450 CYP2D6/genética , Doxepina/envenenamiento , Adulto , Antidepresivos Tricíclicos/sangre , Antidepresivos Tricíclicos/farmacocinética , Doxepina/análogos & derivados , Doxepina/sangre , Doxepina/farmacocinética , Toxicología Forense , Genotipo , Humanos , MasculinoRESUMEN
A simple, rapid and sensitive HPLC method was developed and validated for the determination of four tricyclic antidepressants (TCAs): amitriptyline, doxepin, clomipramine (CLO) and imipramine, in pharmaceutical formulations and biological fluids. A Kromasil C(8 )analytical column (250 x 4 mm, 5 microm) was used for the separation, with a mobile phase consisting of 0.05 M CH(3)COONH(4) and CH(3)CN (45:55 v/v) delivered at 1.5 mL/min isocratically. Quantification was performed at 238 nm, with bromazepam (1.5 ng/microL) as the internal standard. The determination of TCAs in blood plasma was performed after protein precipitation. Urine analysis was performed by means of SPE using Lichrolut RP-18 Merck cartridges providing high absolute recoveries (> 94%). Direct analysis of urine was also performed after two-fold dilution. The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between-day precision (n = 5) revealed RSD <13%. Recoveries from biological samples ranged from 91.0 to 114.0%. The absolute detection limit of the method was calculated as 0.1-0.6 ng in blood plasma and 0.2-0.5 ng in extracted urine or 0.4-0.7 in diluted urine. The method was applied to real samples of plasma from a patient under CLO treatment.
Asunto(s)
Antidepresivos Tricíclicos/análisis , Antidepresivos Tricíclicos/farmacocinética , Técnicas de Química Analítica/métodos , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Urinálisis/métodos , Amitriptilina/análisis , Amitriptilina/farmacocinética , Clomipramina/análisis , Clomipramina/farmacocinética , Doxepina/análisis , Doxepina/farmacocinética , Humanos , Imipramina/análisis , Imipramina/farmacocinética , Modelos Químicos , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrofotometría/métodos , Factores de TiempoRESUMEN
INTRODUCTION: CYP2D6 gene duplication causing ultrafast metabolism is one reason for failure in responding to CYP2D6-metabolized antidepressants. We studied the effect of the CYP2D6 duplication genotype on doxepin pharmacokinetics and platelet serotonin uptake and concentrations. METHODS: Pharmacokinetics of trans (E)- and cis (Z)-doxepin and N-desmethyldoxepin were analyzed after a single dose of 75 mg doxepin in 11 ultrafast metabolizers (UM), 11 extensive metabolizers (EM) and 3 poor metabolizers (PM), identified by genotyping for CYP2D6 alleles *2, *3, *4, *5, *6, *9, *10, *35, *41 and specific analyses to characterize gene duplication. Platelet serotonin concentrations were measured by HPLC. RESULTS: A trend for lower AUC of the active principle (sum of doxepin and N-desmethyldoxepin) in UMs versus EMs was detected (575 versus 1,000 nmol h/l, P=0.07), mainly due to the differences in desmethyldoxepin concentrations (P=0.003). Stereoselective analysis showed a significant effect of the UM genotype on (E)-doxepin pharmacokinetic parameters whereas those of (Z)-doxepin did not differ between the CYP2D6 genotype groups. The 75-mg doxepin dose had no effect on platelet serotonin concentration and uptake, but serotonin concentrations in platelets were significantly higher in UM in comparison to the EM and PM groups. At baseline, these concentrations were 462, 399, and 292 ng/10 platelets in UM, EM and PM (P<0.0001 for trend). CONCLUSIONS: At the same dose, internal exposure to doxepin differed by more than ten-fold between the CYP2D6 genotype groups. CYP2D6 may have an effect on platelet serotonin explained by salvage pathways of 5-methoxytryptamine to serotonin mediated by CYP2D6; however, this finding requires further confirmatory experiments.
Asunto(s)
Antidepresivos Tricíclicos/farmacocinética , Plaquetas/metabolismo , Citocromo P-450 CYP2D6/genética , Doxepina/farmacocinética , Serotonina/sangre , Antidepresivos Tricíclicos/farmacología , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Doxepina/farmacología , Duplicación de Gen , Genotipo , Humanos , Masculino , Valores de ReferenciaRESUMEN
The aim of this study was to develop simplified positron emission tomography measurement using [(11)C]doxepin ([(11)C]DOX) to evaluate histamine H(1) receptors (H1Rs) in human brains. We evaluated the correlation between the distribution volume (DV) of [(11)C]DOX, estimated quantitatively with a two-compartment model, and the [(11)C]DOX uptake obtained at various time intervals and normalized using the metabolite-corrected plasma radioactivity. We found that the static 70- to 90-min images normalized using the plasma radioactivity at 10 min postinjection reflected the DV of [(11)C]DOX-H1R binding.
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Doxepina/farmacocinética , Interpretación de Imagen Asistida por Computador/métodos , Tomografía de Emisión de Positrones/métodos , Receptores Histamínicos H1/metabolismo , Adulto , Algoritmos , Radioisótopos de Carbono , Humanos , Masculino , Tasa de Depuración Metabólica , Modelos Biológicos , Radiofármacos/farmacocinética , Estadística como Asunto , Distribución TisularRESUMEN
The role of metabolites in bioequivalence studies has been a contentious issue for many years. Many papers have published recommendations for the use of metabolite data based on anecdotal evidence from the results of bioequivalence studies. Such anecdotal evidence has validity, but the arguments lack weight because the "correct" answers are always unknown. A more promising area of exploration is recommendations based on simulated bioequivalence studies for which the "correct" answers are known, given the assumptions. A review of the literature, however, reveals scant evidence of attempts to apply to real data the pharmacokinetic principles on which the recommendations from simulated studies relied. We therefore applied those principles (based on estimates of intrinsic clearance after oral administration of the parent drug) to four bioequivalence studies from our archives, in which the parent drug and at least one metabolite were monitored. In each case, the outcome is discussed in the context of the complexity of the metabolic processes that impact on the parent drug and the metabolite(s) during the first passage from the intestinal lumen to the systemic circulation. Our observation is that no simple generalization can be made such that each drug/metabolite combination must be examined individually. Our recommendation, however, is that in the interests of safety, bioequivalence decision-making should be based on the parent drug whenever possible.