RESUMEN
The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUCinf ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for Cmax (2.64-3.52) and AUCinf (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUCinf ratio with coadministration; however, renal clearance did not change. Cmax , AUCinf , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Interacciones Farmacológicas , Itraconazol/farmacocinética , Oxazolidinonas/farmacocinética , Pirrolidinas/farmacocinética , Hormona Liberadora de Tirotropina/análogos & derivados , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Administración Oral , Adulto , Área Bajo la Curva , Pueblo Asiatico , Transporte Biológico/efectos de los fármacos , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/farmacología , Vías de Eliminación de Fármacos/efectos de los fármacos , Voluntarios Sanos , Hormonas/sangre , Humanos , Itraconazol/administración & dosificación , Itraconazol/farmacología , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Oxazolidinonas/administración & dosificación , Oxazolidinonas/efectos adversos , Oxazolidinonas/metabolismo , Permeabilidad/efectos de los fármacos , Pirrolidinas/administración & dosificación , Pirrolidinas/efectos adversos , Pirrolidinas/metabolismo , Adulto JovenRESUMEN
Central nervous system plays a vital role in regulation of most of biological functions which are abnormally affected in various disorders including cerebral ischemia, Alzheimer's and Parkinson's (AD and PD) worldwide. Cerebral stroke is an extremely fatal and one of the least comprehensible neurological disorders due to limited availability of prospective clinical approaches and therapeutics. Since, some endogenous peptides like thyrotropin-releasing hormone have shown substantial neuroprotective potential, hence present study evaluates the newer thyrotropin-releasing hormone (TRH) analogue L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 for its neuroprotective effects against oxygen glucose deprivation (OGD), glutamate and H2O2 induced injury in pheochromocytoma cell lines (PC-12 cells) and in-vivo ischemic injury in mice. Additionally, the treatment was further analyzed with respect to models of AD and PD in mice. Cerebral ischemia was induced by clamping both bilateral common carotid arteries for ten minutes. Treatment was administered to the mice five minute after restoration of blood supply to brain. Consequential changes in neurobehavioural, biochemical and histological parameters were assessed after a week. L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 showed significant reduction in glutamate, H2O2 and OGD -induced cell death in concentration and time dependent manner. Moreover, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 resulted in a substantial reduction in CA1 (Cornus Ammonis 1) hippocampal neuronal cell death, inflammatory cytokines, TNF-α, IL-6 and oxidative stress in hippocampus. In addition, L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 was found to be protective in two acute models of AD and PD as well these findings demonstrate the neuroprotective potential of L-pGlu-(1-benzyl)-l-His-l-Pro-NH2 in cerebral ischemia and other diseases, which may be mediated through reduction of excitotoxicity, oxidative stress and inflammation.
Asunto(s)
Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Hormona Liberadora de Tirotropina/análogos & derivados , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Catalepsia/complicaciones , Catalepsia/tratamiento farmacológico , Catalepsia/patología , Catalepsia/fisiopatología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Glucosa/deficiencia , Ácido Glutámico/toxicidad , Haloperidol , Hipocampo/efectos de los fármacos , Hipocampo/fisiopatología , Mediadores de Inflamación/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Trastornos de la Memoria/complicaciones , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/patología , Trastornos de la Memoria/fisiopatología , Ratones , Modelos Biológicos , Actividad Motora/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/patología , Oxígeno/toxicidad , Células PC12 , Ratas , Escopolamina , Hormona Liberadora de Tirotropina/química , Hormona Liberadora de Tirotropina/farmacología , Hormona Liberadora de Tirotropina/uso terapéuticoRESUMEN
Rovatirelin ([1-[-[(4S,5S)-(5-methyl-2-oxo oxazolidin-4-yl) carbonyl]-3-(thiazol-4-yl)-l-alanyl]-(2R)-2-methylpyrrolidine) is a novel synthetic agent that mimics the actions of thyrotropin-releasing hormone (TRH). The aim of this study was to investigate the electrophysiological and pharmacological effects of rovatirelin on the central noradrenergic system and to compare the results with those of another TRH mimetic agent, taltirelin, which is approved for the treatment of spinocerebellar degeneration (SCD) in Japan. Rovatirelin binds to the human TRH receptor with higher affinity (Ki=702nM) than taltirelin (Ki=3877nM). Rovatirelin increased the spontaneous firing of action potentials in the acutely isolated noradrenergic neurons of rat locus coeruleus (LC). The facilitatory action of rovatirelin on the firing rate in the LC neurons was inhibited by the TRH receptor antagonist, chlordiazepoxide. Reduction of the extracellular pH increased the spontaneous firing of LC neurons and rovatirelin failed to increase the firing frequency further, indicating an involvement of acid-sensitive K+ channels in the rovatirelin action. In in vivo studies, oral administration of rovatirelin increased both c-Fos expression in the LC and extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC) of rats. Furthermore, rovatirelin increased locomotor activity. The increase in NA level and locomotor activity by rovatirelin was more potent and longer acting than those by taltirelin. These results indicate that rovatirelin exerts a central nervous system (CNS)-mediated action through the central noradrenergic system, which is more potent than taltirelin. Thus, rovatirelin may have an orally effective therapeutic potential in patients with SCD.