Abstract
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.
Highlights
Herbal medicine often changes the disposition of concomitant drugs by inducing or inhibiting drug-metabolizing enzymes [1,2]
THB exhibited more potent inhibitory activity against CYP2D6 (IC50 values: 0.97 μM; 95% CI: 0.76–1.23 μM) than BBR
Our data reveals that BBR exhibits selective inhibition of CYP2D6 with 11.9 μM of IC50 observed in direct cytochrome P450 (CYP) inhibition assay
Summary
Herbal medicine often changes the disposition of concomitant drugs by inducing or inhibiting drug-metabolizing enzymes [1,2]. The herb-drug interaction (HDI) involving the inhibition of major cytochrome P450 (CYP) isozymes (i.e., 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5) may increase the drug concentration to a toxic level [3,4,5], causing unexpected adverse effects [6]. This HDI results from the herbal medicine itself and its metabolites, which is called metabolism-dependent inhibition (MDI). An in vitro study demonstrated the metabolism of BBR into TFD and DMB by CYP1A2, 2D6, and 3A4 isozymes using human liver microsomes (HLM) and recombinant human CYPs [27]
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