| Metabolism and disposition of a gamma-aminobutyric acid type A receptor partial agonist in humans. | |
| | |
MedLine Citation:
|
PMID: 18180269 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The metabolism and disposition of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-indole-3-carboxamide (1), a potent subtype-selective partial agonist at the gamma-aminobutyric acid type A receptor complex, were elucidated in humans following a p.o. dose of N-[3-fluoro-4-[2-(propylamino)ethoxy]phenyl]-4,5,6,7-tetrahydro-4-oxo-1H-[3-(14)C]indole-3-carboxamide monomethane-sulfonate ([(14)C]1). Overall, 1 was well tolerated, with approximately twice as much radioactivity excreted in feces (64.8 +/- 13.3%) as in urine (28.4 +/- 8.8%). Across subjects, the oral clearance of 1 was composed of both renal (10%) and metabolic (< or =90%) components, with the biotransformation of 1 happening predominately via oxidative deamination to either 2-fluoro-4-[(4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)-amino]-phenoxy acetic acid (2) or 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid [3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-amide (3) and minimally by aliphatic hydroxylation and carbamate formation. Active renal secretion of 1 was observed as its unbound renal clearance was 6-fold greater than the glomerular filtration rate. Experiments using human hepatic in vitro systems were undertaken to better understand the enzyme(s) involved in the clinically observed oxidative biotransformation pathways. N-Dealkylation of 1, the principal metabolic route observed in vivo, was found to be predominately monoamine oxidase-B-mediated with the resulting putative aldehyde intermediate undergoing subsequent oxidation to 2 or reduction to 3. |
| | |
Authors:
|
Christopher L Shaffer; Mithat Gunduz; Alfin D Vaz; Karthik Venkatakrishnan; Aaron H Burstein |
Related Documents
:
|
16517729 - Signaling through mutants of the iga receptor cd89 and consequences for fc receptor gam... 20504609 - Excitatory amino acids release endogenous acetylcholine from rat striatal slices: regul... 10800729 - Generic models for radionuclide dosimetry: 11c-, 18f- or 75se-labelled amino acids. 17558289 - Corelease of gaba/glycine in lamina-x of the spinal cord of neonatal rats. 6311379 - Calcergy and calciphylaxis: timed appearance of gamma-carboxyglutamic acid and osteocal... 16483879 - Metabolism of gamma-hydroxybutyrate to d-2-hydroxyglutarate in mammals: further evidenc... 18258219 - Versatile acetylation of carbohydrate substrates with bench-top sulfonic acids and appl... 1779619 - A comparative study of sialyloligosaccharides isolated from sialidosis and galactosiali... 5764339 - Spirochaeta aurantia, a pigmented, facultatively anaerobic spirochete. |
Publication Detail:
|
Type: Comparative Study; Journal Article Date: 2008-01-07 |
Journal Detail:
|
Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 36 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2008 Apr |
Date Detail:
|
Created Date: 2008-03-24 Completed Date: 2008-06-23 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
|
Languages: eng Pagination: 655-62 Citation Subset: IM |
Affiliation:
|
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Eastern Point Road, MS 8220-4186, Groton, CT 06340, USA. christopher.l.shaffer@pfizer.com |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Adolescent Adult GABA Agonists / chemistry*, metabolism* Humans Male Metabolic Networks and Pathways / physiology Microsomes, Liver / metabolism Middle Aged Receptors, GABA-A / agonists*, metabolism* Tissue Distribution / physiology |
| Chemical | |
Reg. No./Substance:
|
0/GABA Agonists; 0/Receptors, GABA-A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Altered pharmacokinetics of cationic drugs caused by down-regulation of renal rat organic cation tra...
Next Document: Species-dependent transport and modulation properties of human and mouse multidrug resistance protei...