title: Guanfu base A, an antiarrhythmic alkaloid of Aconitum coreanum, Is a CYP2D6 inhibitor of human, monkey, and dog isoforms.
abstract: 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.
authors: 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.).
authors: Jianguo
authors: J
authors: Sun
authors: 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.).
authors: Ying
authors: Y
authors: Peng
authors: 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.).
authors: Hui
authors: H
authors: Wu
authors: 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.).
authors: Xueyuan
authors: X
authors: Zhang
authors: 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.).
authors: Yunxi
authors: Y
authors: Zhong
authors: 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.).
authors: Yanan
authors: Y
authors: Xiao
authors: 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.).
authors: Fengyi
authors: F
authors: Zhang
authors: 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.).
authors: Huanhuan
authors: H
authors: Qi
authors: 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.).
authors: Lili
authors: L
authors: Shang
authors: 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.).
authors: Jianping
authors: J
authors: Zhu
authors: 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.).
authors: Yue
authors: Y
authors: Sun
authors: 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.).
authors: Ke
authors: K
authors: Liu
authors: 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.).
authors: Jinghan
authors: J
authors: Liu
authors: 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.).
authors: Jiye
authors: J
authors: A
authors: 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.).
authors: Rodney J Y
authors: RJ
authors: Ho
authors: 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.) guangjiwang@hotmail.com.
authors: Guangji
authors: G
authors: Wang
mesh_terms: D031841:Aconitum / Q000737:chemistry*; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors / Q000494:pharmacology*; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D005260:Female; D000882:Haplorhini; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D020033:Protein Isoforms / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology; D051381:Rats
chemical_list: D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D020033:Protein Isoforms; D003917:Dextrorphan; C040615:Guan-fu base A; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine