title: Metabolism and pharmacokinetics of naronapride (ATI-7505), a serotonin 5-HT(4) receptor agonist for gastrointestinal motility disorders.
abstract: The absorption and disposition of the serotonin 5-HT(4) receptor agonist, naronapride (6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid 1-aza-bicyclo[2,2,2]oct-(R)-3-yl ester dihydrochloride; ATI-7505), were evaluated in healthy males given a single 120-mg oral dose of (14)C-labeled compound. Serial blood samples and complete urine and feces were collected up to 552 h postdose. Naronapride was extensively metabolized, undergoing rapid hydrolysis to 6-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-hexanoic acid (ATI-7500) with stoichiometric loss of quinuclidinol. ATI-7500 was either N-glucuronidated on the phenyl ring or its hexanoic acid side chain underwent two-carbon cleavage, probably through a β-oxidation metabolic pathway, to form 4-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-butanoic acid (ATI-7400). ATI-7400 underwent further side-chain oxidation to form 2-[(3S,4R)-4-(4-amino-5-chloro-2-methoxy-benzoylamino)-3-methoxy-piperidin-1-yl]-acetic acid (ATI-7100). Quinuclidinol, ATI-7500, ATI-7400, and ATI-7100 were the major metabolites, with plasma area under the curve values approximately 72-, 17-, 8-, and 2.6-fold that of naronapride. Naronapride, ATI-7500, ATI-7400, and ATI-7100 accounted for 32.32, 36.56, 16.28, and 1.58%, respectively, of the dose recovered in urine and feces. ATI-7400 was the most abundant radioactive urinary metabolite (7.77%), and ATI-7500 was the most abundant metabolite in feces (35.62%). Fecal excretion was the major route of elimination. Approximately 32% of the dose was excreted unchanged in feces. Naronapride, ATI-7500, and quinuclidinol reached peak plasma levels within 1 h postdose. Peak ATI-7400 and ATI-7100 concentrations were reached within 1.7 h, suggesting rapid ATI-7500 metabolism. Naronapride plasma terminal half-life was 5.36 h, and half-lives of the major metabolites ranged from 17.69 to 33.03 h. Naronapride plasma protein binding was 30 to 40%. The mean blood/plasma radioactivity ratio indicated minimal partitioning of (14)C into red blood cells.
authors: ARYx Therapeutics, 6300 Dumbarton Circle, Fremont, CA 94555, USA. sbowersox@aryx.com
authors: S Scott
authors: SS
authors: Bowersox
authors: Luke K
authors: LK
authors: Lightning
authors: Satish
authors: S
authors: Rao
authors: Monica
authors: M
authors: Palme
authors: Dave
authors: D
authors: Ellis
authors: Renee
authors: R
authors: Coleman
authors: Adrian M
authors: AM
authors: Davies
authors: Padmapriya
authors: P
authors: Kumaraswamy
authors: Pascal
authors: P
authors: Druzgala
mesh_terms: D000818:Animals; D001549:Benzamides / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011812:Quinuclidines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051381:Rats; D044422:Receptors, Serotonin, 5-HT4 / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D001549:Benzamides; D011812:Quinuclidines; D017366:Serotonin Receptor Agonists; C517618:ATI 7505; D044422:Receptors, Serotonin, 5-HT4