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1.
Drug Metab Dispos ; 48(8): 724-734, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32482623

RESUMEN

Despite a recent expansion in the recognition of the potential utility of coproporphyrin (CP) as an endogenous biomarker of organic anion-transporting polypeptide (OATP) 1B activity, there have been few detailed studies of CP's pharmacokinetic behavior and an overall poor understanding of its pharmacokinetic fate from tissues and excretion. Here, we describe the pharmacokinetics of octadeuterium-labeled coproporphyrin I (CPI-d8) in cynomolgus monkeys following oral and intravenous administration. CPI-d8 has a half-life and bioavailability of 7.6 hours and 3.2%, respectively. Cynomolgus monkeys received oral cyclosporin A (CsA) at 4, 20, and 100 mg/kg which yielded maximum blood concentrations (C max) and area under the plasma concentration-time curve (AUC) values of 0.19, 2.5, and 3.8 µM, and 2.7, 10.5, and 26.6 µM·h, respectively. The apparent CsA-dose dependent increase in the AUC ratio of CPI-d8 (1.8, 6.2, and 10.5), CPI (1.1, 1.4, and 4.4), and CPIII (1.1, 1.8, and 4.6) at 4, 20, and 100 mg, respectively. In contrast, the plasma concentrations of CPI and CPIII were generally not affected by intravenous administration of the renal organic anion and cation transporter inhibitors (probenecid and pyrimethamine, respectively). In addition, tritium-labeled coproporphyrin I ([3H]CPI) showed specific and rapid distribution to the liver, intestine, and kidney after an intravenous dose in mice using quantitative whole-body autoradiography. Rifampin markedly reduced the liver and intestinal uptake of [3H]CPI while increasing the kidney uptake. Taken together, these results suggest that hepatic OATP considerably affects the disposition of CPI in animal models, indicating CPI is a sensitive and selective endogenous biomarker of OATP inhibition. SIGNIFICANCE STATEMENT: This study demonstrated that coproporphyrin I (CPI) has favorable oral absorption, distribution, and elimination profiles in monkeys and mice as an endogenous biomarker. It also demonstrated its sensitivity and selectivity as a probe of organic anion-transporting polypeptide (OATP) 1B activity. The study reports, for the first time, in vivo pharmacokinetics, tissue distribution, sensitivity, and selectivity of CPI as an OATP1B endogenous biomarker in animals. The data provide preclinical support for exploration of its utility as a sensitive and selective circulating OATP biomarker in humans.


Asunto(s)
Coproporfirinas/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Administración Intravenosa , Administración Oral , Animales , Área Bajo la Curva , Disponibilidad Biológica , Biomarcadores/análisis , Biomarcadores/metabolismo , Coproporfirinas/análisis , Coproporfirinas/farmacocinética , Ciclosporina/administración & dosificación , Ciclosporina/farmacocinética , Evaluación Preclínica de Medicamentos/métodos , Interacciones Farmacológicas , Semivida , Absorción Intestinal , Riñón/efectos de los fármacos , Riñón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Macaca fascicularis , Masculino , Ratones , Rifampin/administración & dosificación , Distribución Tisular
2.
Bioorg Med Chem Lett ; 27(4): 855-861, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28108251

RESUMEN

As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.


Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Sitios de Unión , Fosfatidilinositol 3-Quinasa Clase I , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Piperazina , Piperazinas/química , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Relación Estructura-Actividad , Triazinas/química
3.
Bioorg Med Chem Lett ; 26(17): 4256-60, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27476421

RESUMEN

Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.


Asunto(s)
Aminas/química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Triazinas/química , Aminas/metabolismo , Aminas/uso terapéutico , Animales , Artritis/tratamiento farmacológico , Artritis/metabolismo , Artritis/patología , Sitios de Unión , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Concentración 50 Inhibidora , Ratones , Simulación del Acoplamiento Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Unión Proteica , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Relación Estructura-Actividad
4.
FEBS J ; 276(5): 1450-8, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19187224

RESUMEN

Leaf extract of Ginkgo biloba (GBE) is increasingly used as a herbal medicine for the treatment of neurodegenerative, cardiovascular and cerebrovascular diseases. Several studies have demonstrated many protective effects of GBE in neurons, the endothelium and liver. In this study, we investigated the molecular mechanisms underlying the effects of GBE in disorders induced by long-term exposure to a high-fat diet (HFD). Rats were fed an HFD with or without the GBE product GBE50 for 19 weeks. We found that GBE50 reduced the development of fatty liver induced by an HFD and inhibited the commonly observed elevation of serum cholesterol and lactate dehydrogenase levels. Transcriptome profiling analysis showed that several genes were modulated by GBE50 in liver, including those involved in lipid metabolism, carbohydrate metabolism, vascular constriction, ion transportation, neuronal systems and drug metabolism. Notably, a number of genes coding for proteins involved in cholesterol metabolism were repressed, and some were upregulated. Fatty acid biosynthesis appeared to be repressed, whereas fatty acid metabolism appeared to be enhanced. In conclusion, using transcriptome profiling analysis, we demonstrated the molecular basis for the pleiotropic effects of GBE50, particularly those involved in lipid metabolism. This study provided new clues for further pharmacological study of GBEs.


Asunto(s)
Grasas de la Dieta/administración & dosificación , Perfilación de la Expresión Génica , Ginkgo biloba/química , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Metabolismo de los Hidratos de Carbono/genética , Colesterol/genética , Colesterol/metabolismo , Grasas de la Dieta/farmacología , Metabolismo de los Lípidos/genética , Hígado/metabolismo , Masculino , Ratas , Ratas Wistar
5.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 27(2): 151-4, 2007 Feb.
Artículo en Chino | MEDLINE | ID: mdl-17343004

RESUMEN

OBJECTIVE: To preliminarily investigate the influence of hypoxia on human umbilical vein endothelial cells (HUVECs), and the effect of Ginkgo biloba extract 50 (GBE50) on it. METHODS: Flow cytometry, TUNEL, RT-PCR, Western blot, etc. were applied, to study the effect of hypoxia and GBE50 on endothelial cells. RESULTS: After being interfered by hypoxia for 24 h, the levels of reactive oxygen species (ROS) in HUVECs and the apoptotic rate either in the early or in the late stage significantly increased, and accompanied with the increased levels of endothelin-1 mRNA (ET-1) and endothelial oxide synthase (eNOS) protein. However, when HUVECs were pretreated with GBE50 (25 [microg/ml) 4 h before hypoxia, the apoptotic rate in the early or late stage and expression of ET-1 mRNA significantly decreased (P < 0.05), and the heightened ROS level and eNOS expression partially decreased (P > 0.05). CONCLUSION: Hypoxia can induce endothelial dysfunction, which could be partially or significantly reversed by GBE50, it shows a certain protective effect on hypoxia induced endothelial dysfunction.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Células Endoteliales/efectos de los fármacos , Ginkgo biloba/química , Western Blotting , Hipoxia de la Célula , Células Cultivadas , Células Endoteliales/metabolismo , Endotelina-1/biosíntesis , Endotelina-1/genética , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Endotelio Vascular/fisiopatología , Depuradores de Radicales Libres/farmacología , Humanos , Hojas de la Planta/química , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Especies Reactivas de Oxígeno/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
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