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.
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 (1R,5S)-2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-4[(14)C]-3- benzazepine hydrochloride ([(14)C]1) orally. Although both species chiefly (>or=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 t(1/2) for both 1 and total radioactivity. In monkeys, in which only M5 was formed, double-humped plasma concentration-time curves were absent, and moderate t(1/2) 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.
Shaffer
Christopher L
CL
Department of 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
Gunduz
Mithat
M
Ryder
Tim F
TF
O'Connell
Thomas N
TN
D000818:Animals; D001552:Benzazepines / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D001921:Brain / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D020719:Glucuronides / Q000097:blood / Q000737:chemistry* / Q000302:isolation & purification / Q000652:urine; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D007408:Intestinal Absorption; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013045:Species Specificity; D053719:Tandem Mass Spectrometry
C548662:2,3,4,5-tetrahydro-7-(trifluoromethyl)-1,5-methano-1H-3-benzazepine; D001552:Benzazepines; D020719:Glucuronides; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2