RT Journal Article
SR Electronic
T1 Metabolism and Pharmacokinetics of Naronapride, a Serotonin 5-HT4 Receptor Agonist for Gastrointestinal Motility Disorders
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.110.037564
DO 10.1124/dmd.110.037564
A1 S Scott Bowersox
A1 Luke Lightning
A1 Satish Rao
A1 Monica Palme
A1 David Ellis
A1 Renee Coleman
A1 Adrian M Davies
A1 Padmapriya Kumaraswamy
A1 Pascal Druzgala
YR 2011
UL http://dmd.aspetjournals.org/content/early/2011/03/29/dmd.110.037564.abstract
AB The absorption and disposition of the serotonin 5-HT4 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), were evaluated in healthy males given a single 120-mg oral dose of 14C-labeled compound. Serial blood samples and complete urine and feces were collected up to 552 hr 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 beta-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 AUC 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 hour postdose. Peak ATI-7400 and ATI-7100 concentrations were reached within 1.7 hour, suggesting rapid ATI-7500 metabolism. Naronapride plasma terminal half-life was 5.36 hr, and half-lives of the major metabolites ranged from 17.69 hr to 33.03 hr. Naronapride plasma protein binding was 30 to 40%. Mean blood-to-plasma radioactivity indicated minimal partitioning of 14C into red blood cells.