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1.
Drug Metab Dispos ; 49(9): 780-789, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34330719

RESUMEN

There is a lack of translational preclinical models that can predict hepatic handling of drugs. In this study, we aimed to evaluate the applicability of normothermic machine perfusion (NMP) of porcine livers as a novel ex vivo model to predict hepatic clearance, biliary excretion, and plasma exposure of drugs. For this evaluation, we dosed atorvastatin, pitavastatin, and rosuvastatin as model drugs to porcine livers and studied the effect of common drug-drug interactions (DDIs) on these processes. After 120 minutes of perfusion, 0.104 mg atorvastatin (n = 3), 0.140 mg pitavastatin (n = 5), or 1.4 mg rosuvastatin (n = 4) was administered to the portal vein, which was followed 120 minutes later by a second bolus of the statin coadministered with OATP perpetrator drug rifampicin (67.7 mg). After the first dose, all statins were rapidly cleared from the circulation (hepatic extraction ratio > 0.7) and excreted into the bile. Presence of human-specific atorvastatin metabolites confirmed the metabolic capacity of porcine livers. The predicted biliary clearance of rosuvastatin was found to be closer to the observed biliary clearance. A rank order of the DDI between the various systems upon coadministration with rifampicin could be observed: atorvastatin (AUC ratio 7.2) > rosuvastatin (AUC ratio 3.1) > pitavastatin (AUC ratio 2.6), which is in good agreement with the clinical DDI data. The results from this study demonstrated the applicability of using NMP of porcine livers as a novel preclinical model to study OATP-mediated DDI and its effect on hepatic clearance, biliary excretion, and plasma profile of drugs. SIGNIFICANCE STATEMENT: This study evaluated the use of normothermic machine perfusion (NMP) of porcine livers as a novel preclinical model to study hepatic clearance, biliary excretion, plasma (metabolite) profile of statins, and OATP-mediated DDI. Results showed that NMP of porcine livers is a reliable model to study OATP-mediated DDI. Overall, the rank order of DDI severity indicated in these experiments is in good agreement with clinical data, indicating the potential importance of this new ex vivo model in early drug discovery.


Asunto(s)
Interacciones Farmacológicas , Eliminación Hepatobiliar/fisiología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Inactivación Metabólica/fisiología , Hígado , Animales , Evaluación Preclínica de Medicamentos/instrumentación , Evaluación Preclínica de Medicamentos/métodos , Diseño de Equipo , Técnicas In Vitro/instrumentación , Hígado/metabolismo , Hígado/patología , Tasa de Depuración Metabólica , Perfusión/instrumentación , Perfusión/métodos , Reproducibilidad de los Resultados , Porcinos
2.
Crit Rev Oncol Hematol ; 95(3): 282-96, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25921419

RESUMEN

PURPOSE: Several studies have shown the potential benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients. At present the most effective chemotherapeutic regime in HIPEC for gastric cancer is unknown. The aim of this review was to provide a comprehensive overview of chemotherapeutic agents used for HIPEC in gastric cancer. METHODS: A literature search was conducted using the PubMed database to identify studies on chemotherapy used for HIPEC in gastric cancer patients. RESULTS AND CONCLUSION: The chemotherapeutic regime of choice in HIPEC for gastric cancer has yet to be determined. The wide variety in studies and study parameters, such as chemotherapeutic agents, dosage, patient characteristics, temperature of perfusate, duration of perfusion, carrier solutions, intraperitoneal pressure and open or closed perfusion techniques, warrant more experimental and clinical studies to determine the optimal treatment schedule. A combination of drugs probably results in a more effective treatment.


Asunto(s)
Antineoplásicos/administración & dosificación , Quimioterapia del Cáncer por Perfusión Regional , Hipertermia Inducida , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/tratamiento farmacológico , Humanos , Neoplasias Gástricas/patología
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