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 14C-radiolabeled 5-CNAC (as disodium monohydrate salt).Blood, plasma, urine and feces collected over 7days were analyzed for radioactivity. Metabolite profiles were determined in plasma and excreta and metabolite structures were elucidated by LC–MS/MS, LC–1H 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 (tmax=0.5h; Cmax=9.00±2.74μM (mean±SD, n=6) and almost complete. The elimination half-life (t½) 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 Cmax (35.4±7.9μM) at 0.75h and declined with a half-life of 13.9±4.3h. 5-CNAC accounted for 5.8% of the plasma radioactivity AUC0–24h.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.