RESUMEN
The purpose of this study was to evaluate the pharmacokinetics of oral amitriptyline in horses. Oral amitriptyline (1 mg/kg) was administered to six horses. Blood samples were collected from jugular and lateral thoracic vein at predetermined times from 0 to 24 hr after administration. Plasma concentrations were determined by high-performance liquid chromatography and analyzed using noncompartmental methods. Pharmacodynamic parameters including heart rate, respiration rate, and intestinal motility were evaluated, and electrocardiographic examinations were performed in all subjects. The mean maximum plasma concentration (Cmax ) of amitriptyline was 30.7 ng/ml, time to maximum plasma concentration (Tmax ) 1-2 hr, elimination half-life (t1/2 ) 17.2 hr, area under plasma concentration-time curve (AUC) 487.4 ng ml-1 hr-1 , apparent clearance (Cl/F) 2.6 L hr-1 kg-1 , and apparent volume of distribution (Vd/F) 60.1 L/kg. Jugular vein sampling overestimated the amount of amitriptyline absorbed and should not be used to study uptake following oral administration. Heart rate and intestinal motility showed significant variation (p < .05). Electrocardiography did not provide conclusive results. Further studies are required to discern if multiple dose treatment would take the drug to steady state as expected, consequently increasing plasma concentrations.
Asunto(s)
Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Caballos/metabolismo , Administración Oral , Amitriptilina/administración & dosificación , Amitriptilina/sangre , Animales , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/sangre , Área Bajo la Curva , Femenino , Semivida , Caballos/sangre , MasculinoRESUMEN
ABSTRACT Interactions between herbs and drugs may increase or decrease the pharmacological or toxicological effects of either component. Experimental data on the pharmacokinetic interactions between herbal products and drugs are limited. This study attempted to investigate the effect of Bacopa monnieri Linn. (Brahmi) formulation on the pharmacokinetics of amitriptyline in rats. In this study, rats were randomly divided into two groups (n = 6 each) which were served as a control (amitriptyline alone) and treatment group (amitriptyline with B. monnieri), respectively. Rats in the treatment group received B. monnieri (31 mg/kg/day) whereas the control group received normal saline by oral gavage for seven days before a single intragastric administration of 25 mg/kg amitriptyline. Plasma concentrations of amitriptyline were measured up to 24 h after its administration by a developed and validated high-performance liquid chromatography method. Pretreatment with B. monnieri produced a significant increase in the maximum plasma concentration (Cmax), area under the curve (AUC0-t) and elimination half-life (t1/2) of amitriptyline by 16.8%, 26.5%, and 15.5%, respectively, compared to amitriptyline alone. Moreover, oral clearance and volume of distribution (Vss) were decreased by 26.2% and 15.5% respectively. This study concluded that B.monnieri significantly enhanced the oral bioavailability of amitriptyline in rats.
Asunto(s)
Animales , Masculino , Ratas , Bacopa/efectos adversos , Interacciones Farmacológicas , Amitriptilina/farmacocinética , Plantas Medicinales/clasificación , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión/métodosRESUMEN
The purpose of this study was to investigate cyclobenzaprine pharmacokinetics and to evaluate bioequivalence between two different tablet formulations containing the drug. An open, randomized, crossover, single-dose, two-period, and two-sequence design was employed. Tablets were administered to 23 healthy subjects after an overnight fasting and blood samples were collected up to 240 hours after drug administration. Plasma cyclobenzaprine was quantified by means of an LC-MS/MS method. Pharmacokinetic parameters related to absorption, distribution, and elimination were calculated. Cyclobenzaprine plasma profiles for the reference and test products were similar, as well as absorption pharmacokinetic parameters AUC (reference: 199.4 ng ∗ h/mL; test: 201.6 ng ∗ h/mL), Cmax (reference: 7.0 ng/mL; test: 7.2 ng/mL), and T(max) (reference: 4.5 h; test: 4.6 h). Bioequivalence was evaluated by means of 90% confidence intervals for the ratio of AUC (93%-111%) and C(max) (93%-112%) values for test and reference products, which were within the 80%-125% interval proposed by FDA. Cyclobenzaprine pharmacokinetics can be described by a multicompartment open model with an average rapid elimination half-life (t(1/2)ß) of 3.1 hours and an average terminal elimination half-life (t(1/2)γ) of 31.9 hours.
Asunto(s)
Amitriptilina/análogos & derivados , Antidepresivos/administración & dosificación , Equivalencia Terapéutica , Amitriptilina/administración & dosificación , Amitriptilina/sangre , Amitriptilina/farmacocinética , Antidepresivos/sangre , Antidepresivos/farmacocinética , Cromatografía Líquida de Alta Presión , Depresión/tratamiento farmacológico , Semivida , Voluntarios Sanos , Humanos , Comprimidos/administración & dosificación , Espectrometría de Masas en Tándem , Estados UnidosRESUMEN
BACKGROUND/AIMS: Antidepressants are reported to exhibit antiinflammatory effects. However, mechanisms involved in this action have not been elucidated. Thus, the objectives of the present study were (a) to evaluate the effects of amitriptyline on the acute inflammatory process, and (b) to investigate the participation of α(1)-adrenergic receptors and glucocorticoids as possible mechanisms implicated in the amitriptyline action on inflammation. METHODS AND RESULTS: Single and multiple doses of amitriptyline were administered to rats submitted to the carrageenan-induced paw edema model. The results showed a significant antiedematous reaction to amitriptyline, mainly when administered at each elimination half-life. The next step was to evaluate its effects on leukocyte behavior, using intravital microscopy. Amitriptyline produced a significant effect on leukocyte behavior. To investigate possible mechanisms involved, a glucocorticoid receptor antagonist (RU-486) and an α(1)-adrenergic receptor antagonist (prazosin) were used. RU-486 administration lacked the ability to decrease the amitriptyline antiinflammatory effects in the carrageenan-induced paw edema model. Prazosin pretreatment potentiated the amitriptyline antiinflammatory effect without presenting an effect per se. CONCLUSION: The present study shows the ability of amitriptyline to decrease edema and affect leukocyte behavior in an acute inflammatory process; and, for the first time to our knowledge, we suggest the involvement of α(1)-adrenoceptors in the antiinflammatory effects of amitriptyline.
Asunto(s)
Amitriptilina/farmacología , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Receptores Adrenérgicos alfa 1/efectos de los fármacos , Amitriptilina/administración & dosificación , Amitriptilina/farmacocinética , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Carragenina , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Edema/fisiopatología , Semivida , Inflamación/fisiopatología , Leucocitos/efectos de los fármacos , Leucocitos/metabolismo , Masculino , Microscopía/métodos , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismoRESUMEN
Although it is long known that the tricyclic antidepressants amitriptyline, nortriptyline and imipramine inhibit the noradrenaline transporter and alpha(1)-adrenoceptors with similar affinities, which may lead to self-cancelling actions, the selectivity of these drugs for alpha(1)-adrenoceptor subtypes is unknown. The present study investigates the selectivity of amitriptyline, nortriptyline and imipramine for human recombinant and rat native alpha(1)-adrenoceptor subtypes. The selectivity of amitriptyline, nortriptyline and imipramine was investigated in HEK-293 cells expressing each of the human alpha(1)-subtypes and in rat native receptors from the vas deferens (alpha(1A)), spleen (alpha(1B)) and aorta (alpha(1D)) through [(3)H]prazosin binding, and noradrenaline-induced intracellular Ca(2+) increases and contraction assays. Amitriptyline, nortriptyline and imipramine showed considerably higher affinities for alpha(1A)- (approximately 25- to 80-fold) and alpha(1D)-adrenoceptors (approximately 10- to 25-fold) than for alpha(1B)-adrenoceptors in both contraction and [(3)H]prazosin binding assays with rat native and human receptors, respectively. In addition, amitriptyline, nortriptyline and imipramine were substantially more potent in the inhibition of noradrenaline-induced intracellular Ca(2+) increases in HEK-293 cells expressing alpha(1A)- or a truncated version of alpha(1D)-adrenoceptors which traffics more efficiently towards the cell membrane than in cells expressing alpha(1B)-adrenoceptors. Amitriptyline, nortriptyline and imipramine are much weaker antagonists of rat and human alpha(1B)-adrenoceptors than of alpha(1A)- and alpha(1D)-adrenoceptors. The differential affinities for these receptors indicate that the alpha(1)-adrenoceptor subtype which activation is most increased by the augmented noradrenaline availability resultant from the blockade of neuronal reuptake is the alpha(1B)-adrenoceptor. This may be important for the behavioural effects of these drugs.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 1 , Amitriptilina/farmacología , Antidepresivos Tricíclicos/farmacología , Imipramina/farmacología , Nortriptilina/farmacología , Amitriptilina/farmacocinética , Animales , Antidepresivos Tricíclicos/farmacocinética , Calcio/metabolismo , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Imipramina/farmacocinética , Espacio Intracelular/efectos de los fármacos , Espacio Intracelular/metabolismo , Masculino , Músculo Liso/efectos de los fármacos , Músculo Liso/metabolismo , Nortriptilina/farmacocinética , Ratas , Ratas Wistar , Receptores Adrenérgicos alfa 1/metabolismoRESUMEN
Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing amitriptyline hydrochloride are reviewed. Its therapeutic uses, its pharmacokinetic properties, the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. Literature data indicates that amitriptyline hydrochloride is a highly permeable active pharmaceutical ingredient (API). Data on the solubility according to the current Biopharmaceutics Classification System (BCS) were not fully available and consequently amitriptyline hydrochloride could not be definitively assigned to either BCS Class I or BCS Class II. But all evidence taken together, a biowaiver can currently be recommended provided that IR tablets are formulated with excipients used in existing approved products and that the dissolution meets the criteria defined in the Guidances.
Asunto(s)
Amitriptilina/análisis , Antidepresivos Tricíclicos/análisis , Administración Oral , Amitriptilina/administración & dosificación , Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/administración & dosificación , Antidepresivos Tricíclicos/farmacocinética , Fenómenos Químicos , Química Física , Formas de Dosificación , Excipientes , Isomerismo , Permeabilidad , Sales (Química) , Solubilidad , Equivalencia TerapéuticaRESUMEN
In order to assess the extent and the rate of absorption in bioavailability studies, area under the curve (AUC), experimental maximum concentration (Cmax) and experimental time to reach Cmax (Tmax), are used. But when slow-release formulations are considered, the drug concentration-time curves usually show multiple peaks, and it is difficult to compute a Cmax and Tmax value. In case a Cmax value is computed, important variability in this parameter results in high values in the residual variance of the ANOVA test. So in order to decrease the high variability, average parameters: average concentration (Cav), average maximum concentration (Cmax,av) and Cmax,av x 100/Cav (%Cmax,av), are proposed. These new parameters were applied in a bioavailability study of slow-release amitriptyline formulation.
Asunto(s)
Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacocinética , Disponibilidad Biológica , Adulto , Análisis de Varianza , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Método Doble Ciego , Femenino , Humanos , Masculino , Modelos EstadísticosRESUMEN
Neste artigo é exposto sucintamente aspectos do metabolismo dos antidepressivos tricíclicos (desmetilaçao e hipdroxilaçao) que devem ser levados em conta na interpretaçao das dosagens plasmáticas e efeitos clínicos destes medicamentos
Asunto(s)
Humanos , Masculino , Femenino , Amitriptilina/farmacocinética , Antidepresivos Tricíclicos/farmacología , Antidepresivos Tricíclicos/metabolismo , Clomipramina/farmacocinética , Desipramina/farmacocinética , Doxepina/farmacocinética , Imipramina/farmacocinética , Maprotilina/farmacocinética , Mianserina/farmacocinética , Nortriptilina/farmacocinética , Protriptilina/farmacocinética , Viloxazina/farmacocinéticaRESUMEN
Discute aspectos relevantes à compreensão dos mecanismos por meio dos quais os anticonvulsivantes de segunda geração podem atuar no controle da dor de origem neurópatica.(AU)