| Title | SPECIES DIFFERENCES IN THE BIOTRANSFORMATION OF AN {alpha}4{beta}2 NICOTINIC ACETYLCHOLINE RECEPTOR PARTIAL AGONIST: THE EFFECTS OF DISTINCT GLUCURONIDE METABOLITES ON OVERALL COMPOUND DISPOSITION. | | Author(s) | Shaffer CL, Gunduz M, Ryder TF, O'Connell TN | | Institution | 1 Pfizer Global Research & Development; | | Source | Drug Metab Dispos 2009 Nov 12. | | Abstract | The metabolism and disposition of (1R,5S)-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 investigated in Sprague-Dawley rats and Cynomolgus monkeys receiving [(14)C]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 predominately formed an N-carbamoyl glucuronide (M6), exclusively present in bile (69% of dose), while 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 t(1/2)s for both 1 and total radioactivity. In monkeys, where only M5 was formed, double-humped plasma-concentration time curves were absent and moderate t(1/2)s 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19910512 |
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