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Identification and Characterization of Potent CYP2B6 Inhibitors in Woohwangcheongsimwon Suspension, an Herbal Preparation Used in the Treatment and Prevention of Apoplexy in Korea and China

Department of Pharmacology and PharmacoGenomics Research Center (H.K., K.-B.K., H.-Y.K., S.-J.P., J.-G.S., K.-H.L.) and Department of Biochemistry (S.S.Y.), Inje University College of Medicine, Busan, Korea; Frontier Inje Research for Science and Technology, Inje University, Busan, Korea (S.S.Y., K.-H.L.); School of Agricultural Biotechnology, Seoul National University, Seoul, Korea (H.C., J.-K.M., B.-S.P., J.-H.K.); Department of Biosciences and Biotechnology, IBST, Konkuk University, Seoul, Korea (C.-H.L.); and College of Pharmacy, Wonkwang University, Iksan, Korea (H.S.L.)

Woohwangcheongsimwon is a traditional medicine for treating hypertension, arteriosclerosis, coma, and stroke in China and Korea. To assess potential interactions of herb and drug metabolism, commercially available Woohwangcheongsimwon suspensions were examined for their potential to inhibit the activity of nine human cytochrome P450 enzymes. The Woohwangcheongsimwon suspensions showed strong inhibition of CYP2B6 activity. To identify individual constituents with inhibitory activity, the suspension was partitioned using hexane, ethyl acetate, and dichloromethane, and each fraction was tested for its inhibitory effect on CYP2B6-catalyzed bupropion hydroxylation. The hexane fraction possessed inhibitory activity, and gas chromatography/mass spectrometry analysis identified borneol and isoborneol as major constituents of the hexane fraction. These two terpenoids moderately inhibited CYP2B6-catalyzed bupropion hydroxylase activity in a competitive manner, with K_i values of 9.5 and 5.9 µM, respectively, as well as efavirenz 8-hydroxylase activity, with K_i values of 22 and 26 µM, respectively. Additionally, reconstituted mixtures of borneol and isoborneol, at the same concentrations as in the Woohwangcheongsimwon suspension, had comparable potency in inhibiting bupropion hydroxylation. These in vitro data indicate that Woohwangcheongsimwon preparations contain constituents that can potently inhibit the activity of CYP2B6 and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.