Habenschus Maísa Daniela, Moreira Fernanda de Lima, Lopes Norberto Peporine, de Oliveira Anderson R M
Departamento de Química, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil.
Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil.
Planta Med. 2017 May;83(8):727-736. doi: 10.1055/s-0042-124615. Epub 2017 Jan 10.
Grandisin, a lignan isolated from many species of plants, such as , is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent K value for CYP2C9 was 50.60 µM and those for CYP3A4/5 were 48.71 µM and 31.25 µM using two different probe substrates, nifedipine and midazolam, respectively. The apparent K, k, and k/K ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 µM, 0.037 min, and 5.78 mL · min µmol, respectively, by examining nifedipine oxidation, and 31.53 µM, 0.049 min, and 1.55 mL · min µmol, respectively, by examining midazolam 1'-hydroxylation. These apparent k/K values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC > 200 µM and 100 µM, respectively). In contrast, from a concentration of 4 µM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin-drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked.
格兰迪辛是从多种植物（如……）中分离出的一种木脂素，因其具有抗肿瘤和杀锥虫活性等生物学特性，是一种潜在的候选药物。在本研究中，利用人肝微粒体研究了格兰迪辛对人细胞色素P450酶活性的抑制作用。结果表明，格兰迪辛是CYP2C9的竞争性抑制剂，也是CYP3A4/5的竞争性和基于机制的抑制剂。使用两种不同的探针底物硝苯地平和咪达唑仑时，CYP2C9的表观K值为50.60 μM，CYP3A4/5的表观K值分别为48.71 μM和31.25 μM。通过检测硝苯地平氧化反应，基于机制抑制CYP3A4/5的表观K、k和k/K比值分别为6.40 μM、0.037 min和5.78 mL·min μmol，通过检测咪达唑仑1'-羟化反应，其表观K、k和k/K比值分别为31.53 μM、0.049 min和1.55 mL·min μmol。这些表观k/K值与作为CYP3A4/5基于机制抑制剂的几种治疗药物相当，甚至更高。相反，CYP1A2和CYP2D6的活性并未被格兰迪辛显著抑制（IC分别>200 μM和100 μM）。相比之下，从4 μM的浓度开始，格兰迪辛显著刺激CYP2E1活性。这些结果改进了对格兰迪辛-药物相互作用的预测，表明与CYP3A4/5和CYP2E1代谢的药物相互作用的风险不容忽视。
