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1.
Drug Metab Dispos ; 41(12): 2206-14, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24088325

RESUMEN

The objective of the current study was to evaluate the mechanism of absorption and metabolism of a PEGylated peptide, MRL-1 (46 kDa), after s.c. dosing in dogs and rats. Thoracic lymph duct-cannulated (LDC) dog and rat models were developed that allowed continuous collection of lymph for up to 8 days. When [(3)H]MRL-1 was administered s.c. to LDC dogs, ∼73% of the administered radioactivity was recovered in pooled lymph over a period of 120 hours, suggesting that lymphatic uptake is the major pathway of s.c. absorption for this peptide. In agreement with these data, the systemic exposure of radioactivity related to [(3)H]MRL-1 in LDC dogs was decreased proportionately when compared with that in noncannulated control dogs. After i.v. dosing with [(3)H]MRL-1 in LDC dogs, 20% of the administered radioactivity was recovered in pooled lymph over 168 hours, suggesting some level of recirculation of radioactivity related to [(3)H]MRL-1 from the plasma compartment into the lymphatic system. Experiments conducted in the LDC rat model also resulted in similar conclusions. Analysis of injection site s.c. tissue showed significant metabolism of [(3)H]MRL-1, which provides an explanation for the <100% bioavailability of therapeutic proteins and peptides after s.c. dosing. After s.c. dosing, the major circulating components in plasma were the parent peptide and the PEG-linker [(3)H]MRL-2. The metabolism profiles in lymph were similar to those in plasma, suggesting that the loss of peptide was minimal during lymphatic transport. After i.v. dosing in rats, [(3)H]MRL-1 was metabolized and excreted primarily in the urine as metabolites.


Asunto(s)
Benzopiranos/metabolismo , Sistema Linfático/metabolismo , Absorción , Administración Cutánea , Administración Intravenosa/métodos , Animales , Disponibilidad Biológica , Transporte Biológico/fisiología , Perros , Masculino , Ratas , Ratas Sprague-Dawley
2.
Drug Metab Dispos ; 40(5): 952-62, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22328584

RESUMEN

The mechanism underlying subcutaneous absorption of macromolecules and factors that can influence this process were studied in rats using PEGylated erythropoietins (EPOs) as model compounds. Using a thoracic lymph duct cannulation (LDC) model, we showed that PEGylated EPO was absorbed from the subcutaneous injection site mainly via the lymphatic system in rats, which is similar to previous reports in sheep. After subcutaneous administration, the serum exposure was reduced by ∼70% in LDC animals compared with that in the control animals, and most of the systemically available dose was recovered in the lymph. In both LDC and intact rats, the total radioactivity recoveries in excreta after subcutaneous administration were high (70-80%), indicating that catabolism, not poor absorption, was the main cause for the observed low bioavailability (30-40%). Moreover, catabolism of PEGylated EPO was found with both rat subcutaneous tissue homogenate and lymph node cell suspensions, and a significant amount of dose-related breakdown fragments was found in the lymph of LDC rats. In addition, the bioavailability of PEGylated EPOs was shown to be 2- to 4-fold lower in "fat rats," indicating that physiologic features pertinent to lymphatic transport can have a profound impact on subcutaneous absorption. Limited studies in dogs also suggested similar subcutaneous absorption mechanisms. Collectively, our results suggest that the lymphatic absorption mechanism for macromolecules is probably conserved among commonly used preclinical species, e.g., rats and dogs, and that mechanistic understanding of the subcutaneous absorption mechanism and associated determinants should be helpful in biologic drug discovery and development.


Asunto(s)
Eritropoyetina/metabolismo , Eritropoyetina/farmacocinética , Sistema Linfático/metabolismo , Polietilenglicoles/metabolismo , Polietilenglicoles/farmacocinética , Absorción , Tejido Adiposo/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico , Perros , Descubrimiento de Drogas , Electroforesis en Gel de Poliacrilamida , Eritropoyetina/administración & dosificación , Eritropoyetina/sangre , Inyecciones Subcutáneas , Ganglios Linfáticos/metabolismo , Masculino , Actividad Motora/fisiología , Polietilenglicoles/administración & dosificación , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/sangre , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Especificidad de la Especie , Factores de Tiempo , Distribución Tisular
3.
J Exp Med ; 202(4): 517-27, 2005 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-16103409

RESUMEN

The enzyme 11beta-hydroxysteroid dehydrogenase (HSD) type 1 converts inactive cortisone into active cortisol in cells, thereby raising the effective glucocorticoid (GC) tone above serum levels. We report that pharmacologic inhibition of 11beta-HSD1 has a therapeutic effect in mouse models of metabolic syndrome. Administration of a selective, potent 11beta-HSD1 inhibitor lowered body weight, insulin, fasting glucose, triglycerides, and cholesterol in diet-induced obese mice and lowered fasting glucose, insulin, glucagon, triglycerides, and free fatty acids, as well as improved glucose tolerance, in a mouse model of type 2 diabetes. Most importantly, inhibition of 11beta-HSD1 slowed plaque progression in a murine model of atherosclerosis, the key clinical sequela of metabolic syndrome. Mice with a targeted deletion of apolipoprotein E exhibited 84% less accumulation of aortic total cholesterol, as well as lower serum cholesterol and triglycerides, when treated with an 11beta-HSD1 inhibitor. These data provide the first evidence that pharmacologic inhibition of intracellular GC activation can effectively treat atherosclerosis, the key clinical consequence of metabolic syndrome, in addition to its salutary effect on multiple aspects of the metabolic syndrome itself.


Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Arteriosclerosis/tratamiento farmacológico , Azepinas/administración & dosificación , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Resistencia a la Insulina , Triazoles/administración & dosificación , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Adamantano/administración & dosificación , Animales , Aorta/metabolismo , Arteriosclerosis/complicaciones , Arteriosclerosis/enzimología , Glucemia/efectos de los fármacos , Cortisona/metabolismo , Dieta Aterogénica , Modelos Animales de Enfermedad , Ácidos Grasos/sangre , Hidrocortisona , Insulina/sangre , Masculino , Ratones , Ratones Endogámicos ICR , Ratones Noqueados , Síndrome , Triglicéridos/sangre
4.
Science ; 365(6451): 386-392, 2019 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-31273070

RESUMEN

Ceramides contribute to the lipotoxicity that underlies diabetes, hepatic steatosis, and heart disease. By genetically engineering mice, we deleted the enzyme dihydroceramide desaturase 1 (DES1), which normally inserts a conserved double bond into the backbone of ceramides and other predominant sphingolipids. Ablation of DES1 from whole animals or tissue-specific deletion in the liver and/or adipose tissue resolved hepatic steatosis and insulin resistance in mice caused by leptin deficiency or obesogenic diets. Mechanistic studies revealed ceramide actions that promoted lipid uptake and storage and impaired glucose utilization, none of which could be recapitulated by (dihydro)ceramides that lacked the critical double bond. These studies suggest that inhibition of DES1 may provide a means of treating hepatic steatosis and metabolic disorders.


Asunto(s)
Ceramidas/metabolismo , Hígado Graso/genética , Hígado Graso/metabolismo , Resistencia a la Insulina/genética , Proteínas de la Membrana/genética , Oxidorreductasas/genética , Animales , Ceramidas/química , Ceramidas/genética , Dieta Alta en Grasa/efectos adversos , Eliminación de Gen , Leptina/deficiencia , Ratones , Ratones Mutantes , Esfingolípidos/química , Esfingolípidos/metabolismo
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