Sun Jianguo, Peng Ying, Wu Hui, Zhang Xueyuan, Zhong Yunxi, Xiao Yanan, Zhang Fengyi, Qi Huanhuan, Shang Lili, Zhu Jianping, Sun Yue, Liu Ke, Liu Jinghan, A Jiye, Ho Rodney J Y, Wang Guangji
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines (J.S., Y.P., H.W., X.Z., Y.Z., Y.X., F.Z., H.Q., L.S., J.Z., Y.S., K.L., J.A., G.W.), and Department of Natural Medicinal Chemistry (J.L.), China Pharmaceutical University, Nanjing, China; and Department of Pharmaceutics, University of Washington, Seattle, Washington (R.J.Y.H.).
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines (J.S., Y.P., H.W., X.Z., Y.Z., Y.X., F.Z., H.Q., L.S., J.Z., Y.S., K.L., J.A., G.W.), and Department of Natural Medicinal Chemistry (J.L.), China Pharmaceutical University, Nanjing, China; and Department of Pharmaceutics, University of Washington, Seattle, Washington (R.J.Y.H.)
Drug Metab Dispos. 2015 May;43(5):713-24. doi: 10.1124/dmd.114.060905. Epub 2015 Feb 13.
Guanfu base A (GFA) is a novel heterocyclic antiarrhythmic drug isolated from Aconitum coreanum (Lèvl.) rapaics and is currently in a phase IV clinical trial in China. However, no study has investigated the influence of GFA on cytochrome P450 (P450) drug metabolism. We characterized the potency and specificity of GFA CYP2D inhibition based on dextromethorphan O-demethylation, a CYP2D6 probe substrate of activity in human, mouse, rat, dog, and monkey liver microsomes. In addition, (+)-bufuralol 1'-hydroxylation was used as a CYP2D6 probe for the recombinant form (rCYP2D6), 2D1 (rCYP2D1), and 2D2 (rCYP2D2) activities. Results show that GFA is a potent noncompetitive inhibitor of CYP2D6, with inhibition constant Ki = 1.20 ± 0.33 μM in human liver microsomes (HLMs) and Ki = 0.37 ± 0.16 μM for the human recombinant form (rCYP2D6). GFA is also a potent competitive inhibitor of CYP2D in monkey (Ki = 0.38 ± 0.12 μM) and dog (Ki = 2.4 ± 1.3 μM) microsomes. However, GFA has no inhibitory activity on mouse or rat CYP2Ds. GFA did not exhibit any inhibition activity on human recombinant CYP1A2, 2A6, 2C8, 2C19, 3A4, or 3A5, but showed slight inhibition of 2B6 and 2E1. Preincubation of HLMs and rCYP2D6 resulted in the inactivation of the enzyme, which was attenuated by GFA or quinidine. Beagle dogs treated intravenously with dextromethorphan (2 mg/ml) after pretreatment with GFA injection showed reduced CYP2D metabolic activity, with the Cmax of dextrorphan being one-third that of the saline-treated group and area under the plasma concentration-time curve half that of the saline-treated group. This study suggests that GFA is a specific CYP2D6 inhibitor that might play a role in CYP2D6 medicated drug-drug interaction.
关附甲素（GFA）是从朝鲜紫菀中分离出的一种新型杂环抗心律失常药物，目前正在中国进行IV期临床试验。然而，尚无研究调查GFA对细胞色素P450（P450）药物代谢的影响。我们基于右美沙芬O-去甲基化（一种人、小鼠、大鼠、狗和猴肝微粒体中CYP2D6活性的探针底物），对GFA抑制CYP2D的效力和特异性进行了表征。此外，（+）-布非洛尔1'-羟基化用作重组形式（rCYP2D6）、2D1（rCYP2D1）和2D2（rCYP2D2）活性的CYP2D6探针。结果表明，GFA是CYP2D6的强效非竞争性抑制剂，在人肝微粒体（HLMs）中的抑制常数Ki = 1.20±0.33μM，对人重组形式（rCYP2D6）的Ki = 0.37±0.16μM。GFA也是猴（Ki = 0.38±0.12μM）和狗（Ki = 2.4±1.3μM）微粒体中CYP2D的强效竞争性抑制剂。然而，GFA对小鼠或大鼠的CYP2D没有抑制活性。GFA对人重组CYP1A2、2A6、2C8、2C19、3A4或3A5没有任何抑制活性，但对2B6和2E1有轻微抑制作用。HLMs和rCYP2D6预孵育导致酶失活，GFA或奎尼丁可减弱这种失活。用GFA注射预处理后静脉注射右美沙芬（2mg/ml）的比格犬显示CYP2D代谢活性降低，右啡烷的Cmax为生理盐水处理组的三分之一，血浆浓度-时间曲线下面积为生理盐水处理组的一半。本研究表明，GFA是一种特异性CYP2D6抑制剂，可能在CYP2D6介导的药物相互作用中起作用。
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