RT Journal Article
SR Electronic
T1 Guanfu Base A, an Antiarrhythmic Alkaloid of <em>Aconitum coreanum</em>, Is a CYP2D6 Inhibitor of Human, Monkey, and Dog Isoforms
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 713
OP 724
DO 10.1124/dmd.114.060905
VO 43
IS 5
A1 Jianguo Sun
A1 Ying Peng
A1 Hui Wu
A1 Xueyuan Zhang
A1 Yunxi Zhong
A1 Yanan Xiao
A1 Fengyi Zhang
A1 Huanhuan Qi
A1 Lili Shang
A1 Jianping Zhu
A1 Yue Sun
A1 Ke Liu
A1 Jinghan Liu
A1 Jiye A
A1 Rodney J. Y. Ho
A1 Guangji Wang
YR 2015
UL http://dmd.aspetjournals.org/content/43/5/713.abstract
AB 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.