Quasi-irreversible inhibition of CYP2D6 by berberine

Ha Gyeong Kim, Han Sol Lee, Jang Su Jeon, Young Jae Choi, Yeon Jung Choi, So Yeol Yoo, Eun Yeong Kim, Kiho Lee, Inwha Park, Minkyun Na, Han Jin Park, Seung Woo Cho, Jong Hoon Kim, Jae Young Lee, Sang Kyum Kim

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7 Citations (Scopus)


In our previous study, Hwang-Ryun-Hae-Dok-Tang, which contains berberine (BBR) as a main active ingredient, inhibited cytochrome P450 (CYP) 2D6 in a quasi-irreversible manner. However, no information is available on the detailed mechanism of BBR-induced CYP2D6 inhibition. Thus, the present study aimed to characterize the inhibition mode and kinetics of BBR and its analogues against CYP2D6 using pooled human liver microsomes (HLM). BBR exhibited selective quasi-irreversible inhibition of CYP2D6 with inactivation rate constant (kinact) of 0.025 min−1, inhibition constant (KI) of 4.29 µM, and kinact/KI of 5.83 mL/min/µmol. In pooled HLM, BBR was metabolized to thalifendine (TFD), demethyleneberberine (DMB), M1 (proposed as demethylene-TFD), and to a lesser extent berberrubine (BRB), showing moderate metabolic stability with a half-life of 35.4 min and a microsomal intrinsic clearance of 7.82 µL/min/mg protein. However, unlike BBR, those metabolites (i.e., TFD, DMB, and BRB) were neither selective nor potent inhibitors of CYP2D6, based on comparison of half-maximal inhibitory concentration (IC50). Notably, TFD, but not DMB, exhibited metabolism-dependent CYP2D6 inhibition as in the case of BBR, which suggests that methylenedioxybenzene moiety of BBR may play a critical role in the quasi-irreversible inhibition. Moreover, the metabolic clearance of nebivolol (β-blocker; CYP2D6 substrate) was reduced in the presence of BBR. The present results warrant further evaluation of BBR–drug interactions in clinical situations.

Original languageEnglish
Article number916
Pages (from-to)1-14
Number of pages14
Issue number10
Publication statusPublished - 2020 Oct

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© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science


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