Hydrolysis Is the Dominating In Vivo Metabolism Pathway for Arctigenin: Identification of Novel Metabolites of Arctigenin by LC/MS/MS after Oral Administration in Rats

The phenylpropanoid dibenzylbutyrolactone lignan arctigenin, a key component found in Arctium lappa, or burdock, has been reported with a variety of therapeutic effects including anticancer, anti-inflammation, and antivirus effects. Using LC/MS/MS, three novel metabolites of arctigenin, namely, arctigenic acid, arctigenin-4-O'-glucuronide, and 4-O-demethylarctigenin were identified after oral administration of arctigenin in rats for the first time. Another potential metabolite of arctigenin, arctigenin-4'-O-sulfate, was identified in vitro but not in vivo. Structure of arctigenic acid, the major metabolite of arctigenin, was confirmed by C-13-NMR and H-1-NMR. Rapid hydrolysis in plasma was identified as the major metabolic pathway of arctigenin after its oral administration, with V-max, K-m, and Cl-int in rat plasma determined to be 2.21 +/- 0.12 nmol/min/mg, 89.12 +/- 9.44 mu M, and 24.74 mu L/min/mg, respectively. Paraoxonase 1 was further confirmed to be the enzyme responsible for arctigenin hydrolysis, with Vmax, Km, and Clint determined to be 55.39 +/- 1.49 nmol/min/mg, 300.3 +/- 10.86 mu M, and 184.45 mu L/min/mg, respectively.