Isolation and identification of metabolites of osthole in rats

Abstract

1. Osthole (Ost), one of the major components of Cnidium monnieri (L.) Cusson, is had the structure of an isopentenoxy-coumarin with a range of pharmacological activities. In the present study, the metabolism of Ost in male Sprague-Dawley rats was investigated by identifying Ost metabolites excreted in rat urine.

2. Following an oral dose of 40 mg/kg Ost, 10 phase I and 3 phase II metabolites were isolated from the urine of rats, and their structures identified on the basis of a range of spectroscopic data, including 2D-NMR techniques. These metabolites were fully characterized as 5′-hydroxyl-osthole (M-1), osthenol (M-2), 4′-hydroxyl-osthole (M-3), 3, 5′-dihydroxyl-osthole (M-4), 5′-hydroxyl-osthenol (M-5), 4′-hydroxyl-2′, 3′-dihydro-osthenol (M-6), 4′-hydroxyl-osthenol (M-7), 3, 4′-dihydroxyl-osthole (M-8), 2′, 3′-dihydroxyl-osthole (M-9), 5′-hydroxyl-2′, 3′-dihydroosthole (M-10), osthenol-7-O-β-D-glucuronide (M-11), osthole-4′-O-β-D-glucuronide (M-12) and osthole-5′-O-β-D-glycuronate (M-13). This is the first identification of M-1, M-3 to M-13 in vivo.

3. On the basis of the metabolites profile, a possible metabolic pathway for Ost metabolism in rats has been proposed. This is the first systematic study on the phases I and II metabolites of 8-isopentenoxy-coumarin derivative.

Keywords::

• Osthole
• metabolites
• hydroxylation
• glucuronidation
• hydrogenation