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

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 200 mg 14C 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-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= 0.5 h; Cmax= 9.00 ± 2.74 µM (mean ± SD, n=6) and almost complete. The elimination half-life (t½) was 1.5 ± 1.1 hours. 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 ± 7.9 µM) at 0.75 hours and declined with a half-life of 13.9 ± 4.3 hours. 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