RESUMO
Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50 ] 237 µmol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2-K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ × GBP interaction is not mediated by the renal transporters.
Assuntos
Analgésicos/farmacocinética , Cetirizina/metabolismo , Cetirizina/farmacocinética , Gabapentina/farmacocinética , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Adulto , Analgésicos/administração & dosagem , Analgésicos/sangue , Analgésicos/urina , Área Sob a Curva , Cátions/metabolismo , Cetirizina/administração & dosagem , Estudos Cross-Over , Interações Medicamentosas , Feminino , Gabapentina/administração & dosagem , Gabapentina/sangue , Gabapentina/urina , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/tratamento farmacológico , Proteínas de Transporte de Cátions Orgânicos/genética , Transportador 2 de Cátion Orgânico/genética , Medição da Dor/efeitos dos fármacos , Polimorfismo Genético , Eliminação Renal/efeitos dos fármacos , Simportadores/genética , Simportadores/metabolismoRESUMO
We describe a liquid chromatography-tandem mass spectrometric method (LC-MS/MS) for levocetirizine quantification (I) in human plasma. Sample preparation was made using a fexofenadine (II) addition as internal standard (IS), liquid-liquid extraction using cold dichloromethane, and dissolving the final extract in acetonitrile. I and II (IS) were injected in a C18 column and the mobile phase composed of acetonitrile:water:formic acid (80.00:19.90:0.10, v/v/v) and monitored using positive electrospray source with tandem mass spectrometry analyses. The selected reaction monitoring (SRM) was set using precursor ion and product ion combinations of m/z 389>201 for I and m/z 502>467 for II. The limit of quantification and the dynamic range achieved were 0.5ng/mL and 0.5-500.0ng/mL. Validation results on linearity, specificity, accuracy, precision and stability, as well as its application to the analysis of plasma samples taken up to 48h after oral administration of 5mg of levocetirizine dichloridrate in healthy volunteers demonstrate its applicability to bioavailability studies.
Assuntos
Cetirizina/sangue , Antagonistas dos Receptores Histamínicos H1/sangue , Piperazinas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Adolescente , Adulto , Disponibilidade Biológica , Cetirizina/farmacocinética , Estudos Cross-Over , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Pessoa de Meia-Idade , Piperazinas/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Equivalência TerapêuticaRESUMO
The paper is concerned with the formulation of the antihistamine cetirizine into hydrogels. The cellulose derivatives hydroxyethylcellulose (HEC) and methylcellulose (MC) were employed to prepare hydrogels. As auxiliary substances from the group of humectants are indispensable components of hydrogels, the paper examines their effect (glycerol--GL, propylene glycol--PG, and sorbitol--SO) on the rheological properties and pharmaceutical availability of cetirizine in its formulation into hyrogel. The obtained results show that from the viewpoint of dermal administration for cetirizine at this stage of research hydrogels of the following composition are optimal: 3% HEC + 15% GL and 2.5% MC + 10% SO.
Assuntos
Cetirizina/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Hidrogéis , Excipientes Farmacêuticos , Celulose/análogos & derivados , Química Farmacêutica , Glicerol , Metilcelulose , Propilenoglicol , Reologia , SorbitolRESUMO
El aumento de la prevalencia mundial de las patologías respiratorias alérgicas conlleva un aumento simultáneo en la prescripción de antihistamínicos orales. Los efectos adversos que dichos medicamentos provocan en el sistema nervioso central son muy frecuentes(1), por lo que se presenta una revisión actualizada de los antihistamínicos sistémicos bajo el clásico adagio de la Medicina: "Primum non nocere" ("antes que nada no dañar"). En esta revisión se describe las generalidades de la acción de la histamina en el organismo. Los efectos terapéuticos y secundarios de los antihistamínicos de primera y segunda generación y finalmente se presenta una descripción acabada del nuevo antialérgico epinastina
Assuntos
Humanos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Hipersensibilidade/tratamento farmacológico , Terfenadina/efeitos adversos , Terfenadina/farmacocinética , Astemizol/efeitos adversos , Astemizol/farmacocinética , Loratadina/farmacocinética , Cetirizina/farmacocinéticaRESUMO
The bioavailability of two tablet formulations of cetirizine (Zetir from Abbott and Zyrtek from UCB) were compared in 14 healthy male volunteers who received a single dose of 10 mg of cetirizine dihydrochloride in an open randomized two-period crossover design with a 7-day washout period between doses. Plasma samples were obtained over a 24 h interval and cetirizine concentrations were determined by HPLC with ultraviolet detection. From the plasma cetirizine concentration vs. time curves, AUC(0-24) (area under the concentration vs. time curves from 0 to 24 h), Cmax (maximum achieved concentration), Tmax (time to achieve Cmax), Ke (terminal first order elimination constant), elimination half-life (t1/2) and AUC(0-infinity) (area under the concentration vs. time curves extrapolated to infinity) were obtained. The two cetirizine dihydrochloride tablet brands did not show statistically significant differences in bioavailability as assessed by analysis of AUC(0-24), AUC(0-infinity), Cmax, Tmax, Ke and t1/2 values. Based on these results and on the U.S. Food and Drug Administration requirements [1985, 1993], we conclude that both formulations are bioequivalent.