背景:新益散中药汤剂(XYS)通常用于治疗台湾的过敏性鼻炎患者。茶碱主要被人细胞色素P450(CYP)1A2以高亲和力氧化,并且具有窄的治疗指数。
目的:本研究旨在研究XYS对人CYP1A2催化茶碱氧化(THO)的抑制作用及其对患者的不良反应。
方法:在重组酶系统中研究了人CYP。回顾性分析同时使用XYS对茶碱治疗患者的影响。
结果:在主要的人类肝脏和呼吸道CYPs中,XYS抑制剂优先抑制CYP1A2活性,这决定了茶碱的消除和副作用。在XYS汤的草药成分中,当归含有有效的THO抑制剂。呋喃香豆素欧前胡素在XYS和白垩汤中含量丰富,和非竞争性抑制THO活性,Ki值为77-84nM,高于氟伏沙明(20-52nM),临床上与茶碱相互作用。与欧前胡素相比,对肠道细菌代谢产物黄刺醇的THO抑制作用较弱。与抑制作用的效力一致,对接分析产生的Gold适应度值的顺序为-氟伏沙明>欧前胡素>黄花素。在2017年至2018年期间,201093名茶碱用户中有2.6%使用了XYS。在逆概率加权之后,XYS用户比非XYS用户发生更高的不良影响;特别是,头痛的发生率大约高两倍(比值比(OR),2.14;95%置信区间(CI),1.99-2.30;p<0.001)和心动过速(OR,1.83;95%CI,1.21~2.77;p<0.05)。不规则心跳的发生率增加(OR,1.36;95%CI,1.07-1.72;p<0.05)仅在服用高累积剂量(≥24g)XYS的茶碱使用者中。然而,同时服用XYS的茶碱用户的死亡率低于非XYS用户(或,0.24;95%CI,0.14~0.40;p<0.001)。
结论:XYS含有人CYP1A2抑制剂,在同时接受茶碱和XYS的患者中观察到不良反应。进一步的人体研究对于降低XYS使用者的死亡率和调整茶碱的剂量至关重要。
BACKGROUND: The Xin-yi-san herbal decoction (XYS) is commonly used to treat patients with allergic rhinitis in Taiwan. Theophylline is primarily oxidized with high affinity by human cytochrome P450 (CYP)1A2, and has a narrow therapeutic index.
OBJECTIVE: This study aimed to investigate the inhibition of human CYP1A2-catalyzed theophylline oxidation (THO) by XYS and its adverse effects in patients.
METHODS: Human CYPs were studied in recombinant enzyme systems. The influence of concurrent XYS usage in theophylline-treated patients was retrospectively analyzed.
RESULTS: Among the major human hepatic and respiratory CYPs, XYS inhibitors preferentially inhibited CYP1A2 activity, which determined the elimination and side effects of theophylline. Among the herbal components of XYS decoction, Angelicae Dahuricae Radix contained potent THO inhibitors. Furanocoumarin imperatorin was abundant in XYS and Angelicae Dahuricae Radix decoctions, and non-competitively inhibited THO activity with Ki values of 77‒84 nM, higher than those (20‒52 nM) of fluvoxamine, which clinically interacted with theophylline. Compared with imperatorin, the intestinal bacterial metabolite xanthotoxol caused weaker THO inhibition. Consistent with the potency of the inhibitory effects, the docking analysis generated Gold fitness values in the order-fluvoxamine > imperatorin > xanthotoxol. During 2017‒2018, 2.6 % of 201,093 theophylline users consumed XYS. After inverse probability weighting, XYS users had a higher occurrence of undesired effects than non-XYS users; in particular, there was an approximately two-fold higher occurrence of headaches (odds ratio (OR), 2.14; 95 % confidence interval (CI), 1.99‒2.30; p < 0.001) and tachycardia (OR, 1.83; 95 % CI, 1.21‒2.77; p < 0.05). The incidence of irregular heartbeats increased (OR, 1.36; 95 % CI, 1.07‒1.72; p < 0.05) only in the theophylline users who took a high cumulative dose (≥ 24 g) of XYS. However, the mortality in theophylline users concurrently taking XYS was lower than that in non-XYS users (OR, 0.24; 95 % CI, 0.14‒0.40; p < 0.001).
CONCLUSIONS: XYS contains human CYP1A2 inhibitors, and undesirable effects were observed in patients receiving both theophylline and XYS. Further human studies are essential to reduce mortality and to adjust the dosage of theophylline in XYS users.