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1.
Biopharm Drug Dispos ; 30(4): 185-203, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19544285

RESUMEN

The determination of metabolic pathways of a drug candidate through the identification of circulating and excreted metabolites is vitally important to understanding its physical and biological effects. Knowledge of metabolite profiles of a drug candidate in animals and humans is essential to ensure that animal species used in toxicological evaluations of new drug candidates are appropriate models of humans. The recent FDA final guidance recommends that human oxidative metabolites whose exposure exceeds 10% of the parent AUC at steady-state should be assessed in at least one of the preclinical animal species used in toxicological assessment. Additional toxicological testing on metabolites that have higher exposure in humans than in preclinical species may be required. The metabolite profiles in laboratory animals and humans are generally accomplished by mass balance and excretion studies in which radiolabeled drugs are administered to these species. The biological fluids are collected, analysed for total radioactivity and evaluated for a quantitative profile of metabolites. Thus, these studies not only determine the rates and routes of excretion but also provide very critical information on the metabolic pathways of drugs in preclinical species and humans. In addition, these studies are required by regulatory agencies for the new drug approval process. Despite the usefulness of these radiolabeled mass balance studies, there is little concrete guidance on how to perform or assess these complex studies. This article examines the objectives, utilities and limitations of these studies and how these studies could be used for the determination of the metabolite exposure in animals and humans.


Asunto(s)
Productos Biológicos/análisis , Interacciones Farmacológicas , Tasa de Depuración Metabólica , Preparaciones Farmacéuticas/metabolismo , Estándares de Referencia , Animales , Productos Biológicos/química , Seguridad de Productos para el Consumidor/normas , Composición de Medicamentos , Evaluación Preclínica de Medicamentos , Sedimentos Geológicos , Semivida , Humanos , Tasa de Depuración Metabólica/fisiología , Sistemas de Información Radiológica , Distribución Tisular
2.
Drug Metab Dispos ; 33(1): 83-93, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15502007

RESUMEN

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one); BMS-204352] is an investigational maxi-K channel opener to treat ischemic stroke. This study reports the disposition, metabolism, pharmacokinetics, and protein covalent binding of (14)C-labeled MaxiPost in healthy male volunteers as well as in dogs and rats. After each human subject received a single dose of 10 mg (14)C-labeled BMS-204352 (50 microCi) as a 5-ml intravenous infusion lasting 5 min, the plasma radioactivity concentrations showed a unique profile, wherein the concentration appeared to increase initially, followed by a terminal decline. The mean terminal t(1/2) of plasma radioactivity (259 h) was prolonged compared with that of unchanged parent (37 h). Furthermore, the extractability of radioactivity in plasma decreased over time, reaching approximately 20% at 4 h after dosing. The unextractable radioactivity was covalently bound to plasma proteins through a des-fluoro-des-methyl BMS-204352 lysine adduct. Unchanged BMS-204352 and minor metabolites were identified in plasma extract following protein precipitation. The recovery of the radioactive dose in urine and feces was nearly complete in 14-day collections (approximately 37% in urine and 60% in feces). The N-glucuronide of the parent was the prominent metabolite in urine (16.5% of dose), whereas the parent was a major drug-related component in feces (11% of dose). Similar disposition, metabolism, pharmacokinetic, and protein covalent binding properties of (14)C-labeled BMS-204352 were observed in humans, dogs, and rats.


Asunto(s)
Proteínas Sanguíneas/metabolismo , Indoles/metabolismo , Adulto , Animales , Proteínas Sanguíneas/análisis , Radioisótopos de Carbono/análisis , Radioisótopos de Carbono/metabolismo , Perros , Humanos , Indoles/sangre , Indoles/orina , Masculino , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas
3.
Drug Metab Dispos ; 32(5): 545-51, 2004 May.
Artículo en Inglés | MEDLINE | ID: mdl-15100177

RESUMEN

MaxiPost [(3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indole-2-one), or BMS-204352)] is a potent and specific maxi-K channel opener for potential use to treat stroke. This article describes structural characterization of a major human N-glucuronide metabolite of BMS-204352 and identification of the enzyme responsible for the N-glucuronidation reaction. After intravenous administrations of [(14)C]BMS-204352 (10 mg, 50 microCi) to eight healthy human subjects, one major metabolite M representing an average of 17% of the radioactive dose was excreted in pooled urine collected over 0 to 336 h after dosing. A major biliary metabolite of dogs dosed with [(14)C]BMS-204352 (5 mg/kg), which represented about 33% of the dose, has the same retention time and the same tandem mass spectrometry fragmentation pattern as the human urinary metabolite M. Four hundred fifty micrograms of the metabolite was isolated from the dog bile and analyzed by NMR. Long-range (1)H-(13)C NMR experimentation indicated that the glucuronic acid moiety was at the nitrogen site. The N-glucuronide of BMS-204352 was stable up to 24 h at 37 degrees C in the incubations at different pH values (3.0, 7.4, and 9.0) and with glucuronidases from Escherichia coli and Helix pomatia. Of the seven human UDP-glucuronosyltransferases (UGT) isozymes (1A1, 1A3, 1A4, 1A6, 1A7, 1A10, and 2B7) tested, only UGT2B7 produced metabolite M. UGT2B7-catalyzed N-glucuronidation of BMS-204352 exhibited Michaelis-Menten kinetics with a K(m) of 14.2 microM and V(max) of 0.29 nmol/min. mg of protein. Collectively, these results suggest that amide N-glucuronidation, a major elimination pathway of MaxiPost, is catalyzed by UGT2B7 in humans. This N-glucuronide represents a fully characterized amide N-glucuronide, and glucuronidation at the nitrogen represents a newly identified conjugation reaction for UGT2B7.


Asunto(s)
Amidas/metabolismo , Glucurónidos/metabolismo , Glucuronosiltransferasa/metabolismo , Indoles/metabolismo , Animales , Catálisis , Perros , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Humanos , Indoles/química , Canales de Potasio de Gran Conductancia Activados por el Calcio , Masculino , Canales de Potasio Calcio-Activados/agonistas , Canales de Potasio Calcio-Activados/metabolismo
4.
Toxicol Appl Pharmacol ; 182(3): 188-96, 2002 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-12229863

RESUMEN

This report summarizes the deliberations of a multidisciplinary committee, sponsored by the Pharmaceutical Research and Manufacturers of America, on current "best practices" within the U.S. pharmaceutical industry in assessing the role of drug metabolites as potential mediators of the toxicity of new drug products. Input to the document was obtained from numerous sources, including members of the pharmaceutical industry, academic investigators, and representatives of regulatory agencies who attended a workshop on the subject in November 2000. The overall goal of the paper is to define practical and scientifically based approaches to the use of metabolite data that address contemporary issues in the safety evaluation of drug candidates. Although there remains a lack of consensus on how best to deal with several aspects of this complex subject, this paper raises a number of points to consider, which emphasize the need to treat drug metabolite issues on a case-by-case basis. It is hoped that the discussion will promote continued dialog among industrial scientists and regulators charged with ensuring the clinical safety of new therapeutic agents.


Asunto(s)
Ensayos Clínicos como Asunto/normas , Evaluación de Medicamentos/métodos , Industria Farmacéutica/normas , Preparaciones Farmacéuticas/metabolismo , Animales , Evaluación de Medicamentos/normas , Humanos , Preparaciones Farmacéuticas/normas , Pruebas de Toxicidad , Estados Unidos , United States Food and Drug Administration
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