title: Metabolism and disposition of the oral absorption enhancer 14C-radiolabeled 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC) in healthy postmenopausal women and supplementary investigations in vitro.
abstract: 8-(N-2-hydroxy-5-chlorobenzoyl)-amino-caprylic acid (5-CNAC), a compound lacking pharmacological activity enhances the absorption of salmon calcitonin, when co-administered. Disposition and biotransformation of 5-CNAC was studied in six healthy postmenopausal women following a single oral dose of 200mg (14)C-radiolabeled 5-CNAC (as disodium monohydrate salt). Blood, plasma, urine and feces collected over 7 days were analyzed for radioactivity. Metabolite profiles were determined in plasma and excreta and metabolite structures were elucidated by LC-MS/MS, LC-(1)H NMR, enzymatic methods and by comparison with reference compounds. Oral 5-CNAC was safe and well tolerated in this study population. 5-CNAC absorption was rapid (t(max)=0.5h; C(max)=9.00 ± 2.74 μM (mean ± SD, n=6) and almost complete. The elimination half-life (t(½)) was 1.5 ± 1.1h. The radioactive dose was excreted mainly in urine (≥ 90%) in form of metabolites and 0.071% as intact 5-CNAC. Excretion of radioactivity in feces was minor and mostly as metabolites (<3%). Radioactivity in plasma reached C(max) (35.4 ± 7.9 μM) at 0.75 h and declined with a half-life of 13.9 ± 4.3h. 5-CNAC accounted for 5.8% of the plasma radioactivity AUC(0-24h). 5-CNAC was rapidly cleared from the systemic circulation, primarily by metabolism. Biotransformation of 5-CNAC involved: (a) stepwise degradation of the octanoic acid side chain and (b) conjugation of 5-CNAC and metabolites with glucuronic acid at the 2-phenolic hydroxyl group. The metabolism of 5-CNAC in vivo could be reproduced in vitro in human hepatocytes. No metabolism of 5-CNAC was observed in human liver microsomes.
authors.affiliation: DMPK, Translational Sciences, Novartis Pharma AG, Basel, Switzerland. hans-peter.gschwind@novartis.com
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Gschwind
authors.forename: Ulrike
authors.initials: U
authors.lastname: Glaenzel
authors.forename: Felix
authors.initials: F
authors.lastname: Waldmeier
authors.forename: Bernard
authors.initials: B
authors.lastname: Wirz
authors.forename: Helene D
authors.initials: HD
authors.lastname: Sabia
authors.forename: Franck
authors.initials: F
authors.lastname: Picard
authors.forename: H Markus
authors.initials: HM
authors.lastname: Weiss
authors.forename: Leslie
authors.initials: L
authors.lastname: Choi
authors.forename: Pieter Jacob
authors.initials: PJ
authors.lastname: Swart
authors.forename: Ajithkumar
authors.initials: A
authors.lastname: Vasudevan
authors.forename: Moïse
authors.initials: M
authors.lastname: Azria
mesh_terms: D000042:Absorption; D019540:Area Under Curve; D001711:Biotransformation; D002210:Caprylates / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D005260:Female; D006207:Half-Life; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D017698:Postmenopause / Q000097:blood* / Q000652:urine*; D019275:Radiopharmaceuticals
chemical_list: D002210:Caprylates; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; C031492:octanoic acid