| Biotransformation of an alpha4beta2 nicotinic acetylcholine receptor partial agonist in sprague-dawley rats and the dispositional characterization of its N-carbamoyl glucuronide metabolite. | |
| | |
MedLine Citation:
|
PMID: 19339375 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
The metabolism and disposition of (1S,5R)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an alpha(4)beta(2) nicotinic acetylcholine receptor partial agonist, was determined in Sprague-Dawley rats after oral administration of [(14)C]1. In intact animals, mass balance was achieved within 48 h, with 5 times more radioactivity excreted in urine than in feces. Compound 1 underwent renal and metabolic clearance equally and exhibited a very long half-life attributable to a secondary peak occurring 8 h postdose in its serum concentration-time curve. In bile duct-cannulated (BDC) rats, mass balance was also achieved within 48 h with 73.7, 23.4, and 5.5% of the dose detected in bile, urine, and feces, respectively. Rats metabolized 1 by two primary routes: four-electron oxidation to either four amino acids or a lactam and formation of an N-carbamoyl glucuronide (M6), which was only detected in bile. The presence of M6 solely in bile and the double-humped serum concentration-time curve of 1 suggested the indirect enterohepatic cycling of 1 via M6 after oral administration. To explore this mechanistic hypothesis further, intravenous studies were conducted with 1 in both intact and BDC rats to determine the extent of 1 undergoing indirect enterohepatic cycling via M6. Compared with the pharmacokinetics in intact rats, total serum clearance was higher (1.7-fold) and volume of distribution was lower (1.6-fold) in BDC rats, resulting in a correspondingly shorter (2.5-fold) half-life, with 56% of administered 1 undergoing recirculation, an amount consistent with that (68% of dose) of M6 observed in bile from rats dosed orally with [(14)C]1. |
| | |
Authors:
|
Christopher L Shaffer; Tim F Ryder; Karthik Venkatakrishnan; Ilana K Henne; Thomas N O'Connell |
Related Documents
:
|
2888475 - Distribution and kinetics of 14c-vecuronium in rats and mice. 1987805 - Hemodynamic characterization of conscious and ketamine-anesthetized bile duct-ligated r... 9989275 - Intestinal synthesis and lymphatic secretion of apolipoprotein a-iv after cessation of ... 7169225 - Selective excretion of iga in rat bronchial secretions: lack of significant contributio... 6487695 - Relationship between luteinizing hormone and decidual luteotropin in the maintenance of... 6246695 - The rise of plasma acth induced by ether is mediated through neural pathways entering t... |
Publication Detail:
|
Type: Journal Article Date: 2009-04-01 |
Journal Detail:
|
Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 37 ISSN: 1521-009X ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2009 Jul |
Date Detail:
|
Created Date: 2009-06-22 Completed Date: 2009-09-28 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
|
Languages: eng Pagination: 1480-9 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:
|
Administration, Oral Animals Bile / drug effects, physiology Biotransformation Carbon Radioisotopes / administration & dosage Chromatography, High Pressure Liquid Glucuronides / metabolism Half-Life Rats Rats, Sprague-Dawley Receptors, Nicotinic / drug effects, genetics, metabolism* |
| Chemical | |
Reg. No./Substance:
|
0/Carbon Radioisotopes; 0/Glucuronides; 0/Receptors, Nicotinic; 0/nicotinic receptor alpha4beta2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Secretos de la Buena Vida: processes of dietary change via a tailored nutrition communication interv...
Next Document: Regulation of human CYP2C18 and CYP2C19 in transgenic mice: influence of castration, testosterone, a...