Abstract

1. Leonurine hydrochloride (LH) is derived from an ingredient of Leonurus japonicus Houtt which is widely used for diseases in women.

2. The influence of LH on the activity of cytochrome P450 (CYPs) enzymes was investigated in this study.

3. The effect of LH on CYPs enzyme activities were studied using the enzyme-selective substrates phenacetin (1A2), coumarin (2A6), diclofenac (2C9), S-mephenytoin (2C19), paclitaxel (2C8), dextromethorphan (2D6), chlorzoxazone (2E1) and testosterone (3A4). The IC₅₀ value was calculated to express the strength of inhibition. The inhibition of CYPs was fitted with competitive or non-competitive inhibition models and corresponding parameters were also obtained.

4. LH exerted inhibitory effects on the activity of CYP1A2, 2D6, and 3A4 with the IC₅₀ values of 18.05, 15.13, and 20.09 μM, respectively. The obtained results showed that LH inhibited the activity of CYP1A2 and CYP2D6 via competitive manners (K_i = 8.667 μM and K_i = 7.805 μM, respectively), while LH attenuated the CYP3A4 activity via a non-competitive manner (K_i = 9.507 μM). Moreover, LH showed time-dependent inhibition on CYP3A4 with the K_I/K_inact value of 4.31/0.044 min⁻¹·μM⁻¹.

5. The inhibition of CYP1A2, CYP2D6, and CYP3A4 by LH, demonstrated in vitro, indicated the potential herb–drug interaction. Therefore, pharmacokinetic interactions involving LH and CYP1A2 or CYP2D6 or CYP1A2 substrates are likely to occur.

摘要

1. 益母草碱盐酸盐 (LH) 来源于益母草的一种成分，广泛用于治疗女性疾病。

2. 本研究调查了 LH 对细胞色素 P450 (CYPs) 酶活性的影响。

3. 使用酶选择性底物非那西丁 (1A2)、香豆素 (2A6)、双氯芬酸 (2C9)、S-美苯妥英 (2C19)、紫杉醇 (2C8)、右美沙芬 (2D6)、氯唑沙宗 ( 2E1) 和睾酮 (3A4)。计算IC ₅₀值以表达抑制强度。对CYPs的抑制进行了竞争性或非竞争性抑制模型拟合，并得到了相应的参数。

4. LH 对 CYP1A2、2D6 和 3A4 的活性产生抑制作用，IC ₅₀值分别为 18.05、15.13 和 20.09 μM。所得结果表明，LH 通过竞争方式抑制 CYP1A2 和 CYP2D6 的活性（K _i = 8.667 μM 和K _i = 7.805 μM），而 LH 通过非竞争性方式减弱 CYP3A4 活性（K _i = 9.507 μM ）。此外，LH 对CYP3A4 具有时间依赖性抑制作用，K _I /K _inact值为4.31/0.044 min ^-1 ·μM ^-1。

5. LH 对 CYP1A2、CYP2D6 和 CYP3A4 的抑制作用在体外得到证实，表明存在潜在的草药-药物相互作用。因此，可能会发生涉及 LH 和 CYP1A2 或 CYP2D6 或 CYP1A2 底物的药代动力学相互作用。