Abstract
The metabolism and disposition of (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine (1), an α4β2 nicotinic acetylcholine receptor partial agonist, was investigated in Sprague-Dawley rats and cynomolgus monkeys receiving (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[14C]-3- benzazepine hydrochloride ([14C]1) orally. Although both species chiefly (≥62%) cleared 1 metabolically, species-specific dispositional profiles were observed for both 1 and total radioactivity. Radioactivity was excreted equally in the urine and feces of intact rats but largely (72%) in bile in bile duct-cannulated animals. In monkeys, radioactivity recoveries were 50-fold greater in urine than feces and minimal (<5%) in bile. Both species metabolized 1 similarly: four-electron oxidation to one of four amino acids or two lactams (minor) and glucuronide formation (major). In rats, the latter pathway predominantly formed an N-carbamoyl glucuronide (M6), exclusively present in bile (69% of dose), whereas in monkeys it afforded an N-O-glucuronide (M5), a minor biliary component (4%) but the major plasma (62%) and urinary (42%) entity. In rats, first-pass hepatic conversion of 1 to M6, which was confirmed in rat hepatocytes, and its biliary secretion resulted in the indirect enterohepatic cycling of 1 via M6 and manifested in double-humped plasma concentration-time curves and long t1/2 for both 1 and total radioactivity. In monkeys, in which only M5 was formed, double-humped plasma concentration-time curves were absent, and moderate t1/2 for both 1 and total radioactivity were observed. A seemingly subtle, yet critical, difference in the chemical structures of these two glucuronide metabolites considerably affected the overall disposition of 1 in rats versus monkeys.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.109.030171
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The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
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- P450
- cytochrome P450
- 1
- (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine hydrochloride
- [14C]1
- (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[14C]-3-benzazepine hydrochloride
- 2
- (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-4-oxo-1H-3-benzazepine
- 3
- (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-2-oxo-1H-3-benzazepine
- 4
- (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine-3-carboxaldehyde
- PGRD
- Pfizer Global Research and Development
- RLM
- rat liver microsome
- MLM
- monkey liver microsome
- HPLC
- high-performance liquid chromatography
- LSC
- liquid scintillation counting
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- RCF
- relative centrifugal force
- MRM
- multiple-reaction monitoring
- AUC
- area under the concentration-time curve
- kel
- elimination rate constant
- LC/MS/NMR
- liquid chromatography/mass spectrometry/nuclear magnetic resonance
- CID
- collision-induced dissociation
- EHC
- enterohepatic cycling
- FMO
- FAD-containing monooxygenase.
- Received September 8, 2009.
- Accepted November 6, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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