Disposition and metabolism of [14C]SB-649868, an orexin 1 and 2 receptor antagonist, in humans

Drug Metabolism and Disposition

Volumn 39, Issue 2, 2011, Pages 215-227

  Renzulli, Cecilia ^a   Nash, Mike ^b   Wright, Mark ^b   Thomas, Steven ^b   Zamuner, Stefano ^a   Pellegatti, Mario ^a   Bettica, Paolo ^a   Boyle, Gary ^b  

^a GSK   (Italy)

^b GLAXOSMITHKLINE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2 [(1 [[5 (4 FLUOROPHENYL) 2 METHYL 1,3 THIAZOL 4 YL]CARBONYL] 2 PIPERIDINYL)METHYL] 3,5 DIHYDROXY 3,4 DIHYDRO 1(2H) ISOQUINOLINONE; DRUG METABOLITE; N [[1 [[5 (4 FLUOROPHENYL) 2 METHYL 4 THIAZOLYL]CARBONYL] 2 PIPERIDINYL]METHYL] 4 BENZOFURANCARBOXAMIDE; RADIOPHARMACEUTICAL AGENT; UNCLASSIFIED DRUG; BENZOFURAN DERIVATIVE; CARBON; G PROTEIN COUPLED RECEPTOR; N ((1 ((5 (4 FLUOROPHENYL) 2 METHYL 4 THIAZOLYL)CARBONYL) 2 PIPERIDINYL)METHYL) 4 BENZOFURANCARBOXAMIDE; N-((1-((5-(4-FLUOROPHENYL)-2-METHYL-4-THIAZOLYL)CARBONYL)-2-PIPERIDINYL)METHYL)-4-BENZOFURANCARBOXAMIDE; NEUROPEPTIDE RECEPTOR; OREXIN RECEPTORS; THIAZOLE DERIVATIVE;

ADULT; ARTICLE; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DISPOSITION; DRUG ELIMINATION; DRUG FECES LEVEL; DRUG HALF LIFE; DRUG METABOLISM; DRUG STRUCTURE; DRUG URINE LEVEL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; MALE; MASS SPECTROMETRY; NORMAL HUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; RADIOACTIVITY; SINGLE DRUG DOSE; URINARY EXCRETION; BIOTRANSFORMATION; BLOOD; CHEMICAL STRUCTURE; CHEMISTRY; CLINICAL TRIAL; DRUG ANTAGONISM; FECES; METABOLISM; MIDDLE AGED; ORAL DRUG ADMINISTRATION; TISSUE DISTRIBUTION; URINE;

ADMINISTRATION, ORAL; ADULT; BENZOFURANS; BIOTRANSFORMATION; CARBON RADIOISOTOPES; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; FECES; HUMANS; MALE; MASS SPECTROMETRY; MIDDLE AGED; MOLECULAR STRUCTURE; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, NEUROPEPTIDE; THIAZOLES; TISSUE DISTRIBUTION;

EID: 79251480429     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.110.035386     Document Type: Article

References (17)

1. Bayer A and Maier ME (2004) Synthesis of enamides from aldehydes and amides. Tetrahedron 60:6665-6677.
2. Botta L, Gerber HU, and Schmid K (1985) Measurement of radioactivity in biological experiments, in Drug Fate and Metabolism, Methods and Techniques (Garrett ER and Hirtz JL eds) vol. 5, pp 99-134, Dekker, New York.
3. Bruin GJ, Waldmeier F, Boernsen KO, Pfaar U, Gross G, and Zollinger M (2006) A microplate solid scintillation counter as a radioactivity detector for high performance liquid chromatography in drug metabolism: validation and applications. J Chromatogr A 1133:184-194.
4. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, et al. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437-451.
5. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, and O'Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269-299.
6. Gerrard PA, Porter R, Holland V, Massagrande M, Poffe A, Piccoli L, Bettica P, Corsi M, Hagan F, and Ratti E (2009) Preclinical pharmacology of SB-649868: a novel orexin OX1/OX2 receptor antagonist possessing potent hypnotic activity in rodents and primates. Sleep 32 (Abstract Supplement):A42.
7. Guengerich FP (2003) Cytochrome P450 oxidations in the generation of reactive electrophiles: epoxidation and related reactions. Arch Biochem Biophys 409:59-71.
8. Kalgutkar AS and Didiuk MT (2009) Structural alerts, reactive metabolites, and protein covalent binding: how reliable are these attributes as predictors of drug toxicity? Chem Biodivers 6:2115-2137.
9. Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y, et al. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 6:161-225.
10. Kilduff TS and Peyron C (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci 23:359-365.
11. Kobayashi T, Sugihara J, and Harigaya S (1987) Mechanism of metabolic cleavage of a furan ring. Drug Metab Dispos 15:877-881.
12. Lammert C, Einarsson S, Saha C, Niklasson A, Bjornsson E, and Chalasani N (2008) Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals. Hepatology 47:2003-2009.
13. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, and Mignot E (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98:365-376.
14. Oliveira EJ and Watson DG (2000) Liquid chromatography-mass spectrometry in the study of the metabolism of drugs and other xenobiotics. Biomed Chromatogr 14:351-372.
15. Roffey SJ, Obach RS, Gedge JI, and Smith DA (2007) What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs. Drug Metab Rev 39:17-43.
16. Uetrecht J (2008) Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol 21:84-92.
17. Zhang D, Krishna R, Wang L, Zeng J, Mitroka J, Dai R, Narasimhan N, Reeves RA, Srinivas NR, and Klunk LJ (2005) Metabolism, pharmacokinetics, and protein covalent binding of radiolabeled MaxiPost (BMS-204352) in humans. Drug Metab Dispos 33:83-93.