Pharmacokinetics and Urine Metabolite Identification of Dehydroevodiamine in the Rat

Abstract

This study investigates the oral bioavailability and characterizes urine metabolites of dehydroevodiamine (DeHE), one of the bioactive alkaloids isolated from the fruit of Evodia rutaecarpa . A freely moving rat model coupled with an automated blood sample system was used to evaluate the pharmacokinetics of DeHE. High-performance liquid chromatography (HPLC), mass spectrometry (MS), and nuclear magnetic resonance (NMR) spectrometry were applied to determine DeHE and its metabolites. The averaged oral bioavailability of DeHE (100 and 500 mg/kg) in the freely moving rats was approximately 15.35%. Cumulative fecal and urinary excretions of unchanged DeHE were 6 and 0.5%, respectively, after a single oral dose (500 mg/kg) of DeHE. The protein binding of DeHE in rat plasma was 65.6 ± 6.5%. Six metabolites, including five DeHE-O-glucuronides and one DeHE-sulfate, were identified after oral administration. The structures of two glucuronide conjugates, DeHE-10-O-glucuronide (M3) and DeHE-11-O-glucuronide (M4), and one sulfate conjugate, DeHE-12-sulfate (M6), were assigned. The findings indicate that the oral bioavailability of DeHE was much higher than that of evodiamine, and hydroxylation and conjugative metabolism were essential for the urinary elimination of DeHE.