Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.
Exploration of cytochrome P450 inhibition mediated drug-drug interaction potential of kratom alkaloids.
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DOI：
10.1016/j.toxlet.2019.11.005
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发表时间：
2020-02-01
影响因子：
3.5
通讯作者：
Avery BA
中科院分区：
文献类型：
--
作者：
Kamble SH;Sharma A;King TI;Berthold EC;León F;Meyer PKL;Kanumuri SRR;McMahon LR;McCurdy CR;Avery BA
用人肝微粒体(HLMS)研究了主要生物碱：三尖杉碱(MTG)、五味子碱(SPG)、五角花碱(SPC)、鸡冠花碱(COR)、7-羟基三尖杉碱(7HMG)和青藤碱(Pay)对细胞色素P450的体外抑制作用，以了解它们的药物相互作用潜力。将CYP1A2、2C8、2C9、2C19、2D6和3A4/5的CYP450异构体特异性底物孵育在含或不含生物碱的HLMS中。为每一种异构体生成初步的细胞色素P450抑制(IC50)数据。此外，还测定了MTG和COR的抑制类型和抑制常数(Ki)的估算。在供试生物碱中，甲氨蝶呤和COR对细胞色素P450有较强的抑制作用(IC50值分别为2.2和4.2μM)。甲氨蝶呤和COR对细胞色素P450 2 D6活性均表现出竞争性抑制作用，其Ki分别为1 1和2 8μM。SPG和Pay对CYP2D6活性有中等程度的抑制作用。此外，SPC、MTG和SPG对CYP2C19活性也有中等程度的抑制作用。有趣的是，当以睾酮为探针底物时，仅观察到COR、Pay和MTG对咪达唑仑羟基酶CYP3A4/5的抑制作用，而没有观察到抑制作用。综上所述，MTG和COR在联合给药时可能会导致临床上显著的不良药物相互作用，这些药物基本上是由CYP2D6代谢的。
In vitro cytochrome P450 inhibition of major kratom alkaloids: mitragynine (MTG), speciogynine (SPG), speciocilliatine (SPC), corynantheidine (COR), 7-hydroxymitragynine (7HMG) and paynantheine (PAY) was evaluated using human liver microsomes (HLMs) to understand their drug-drug interaction potential. CYP450 isoform-specific substrates of CYP1A2, 2C8, 2C9, 2C19, 2D6, and 3A4/5 were incubated in HLMs with or without alkaloids. Preliminary CYP450 inhibition (IC50) data were generated for each of these isoforms. In addition, the type of inhibition and estimation of the inhibition constants (Ki) of MTG and COR were determined. Among the tested alkaloids, MTG and COR were potent inhibitors of CYP2D6 (IC50, 2.2 and 4.2 μM, respectively). Both MTG and COR exhibited competitive inhibition of CYP2D6 activity and the Ki were found to be 1.1 and 2.8 μM, respectively. SPG and PAY showed moderate inhibition of CYP2D6 activity. Additionally, moderate inhibitory effects by SPC, MTG, and SPG were observed on CYP2C19 activity. Interestingly, inhibition of only midazolam hydroxylase CYP3A4/5 activity by COR, PAY, and MTG was observed while no inhibitory effect was observed when testosterone was used as a probe substrate. In conclusion, MTG and COR may lead to clinically significant adverse drug interactions upon coadministration of drugs that are substantially metabolized by CYP2D6.
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影响因子：
--
作者：
Cinosi E;Martinotti G;Simonato P;Singh D;Demetrovics Z;Roman-Urrestarazu A;Bersani FS;Vicknasingam B;Piazzon G;Li JH;Yu WJ;Kapitány-Fövény M;Farkas J;Di Giannantonio M;Corazza O
通讯作者：
Corazza O
DOI：
10.3390/molecules16097344
发表时间：
2011-08-29
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Kong WM;Chik Z;Ramachandra M;Subramaniam U;Aziddin RE;Mohamed Z
通讯作者：
Mohamed Z
影响因子：
33.9
作者：
Olsen, Emily O'Malley;O'Donnell, Julie;Wilson, Nana
通讯作者：
Wilson, Nana
影响因子：
2.5
作者：
Kronstrand, Robert;Roman, Markus;Eriksson, Anders
通讯作者：
Eriksson, Anders
影响因子：
2.9
作者：
Lydecker, Alicia G.;Sharma, Abhisheak;Boyer, Edward W.
通讯作者：
Boyer, Edward W.