He Xiaoai, Luo Xi, Liu Zhi, Hu Gaoyun, Cheng Zeneng
Haikou People's Hospital and Affiliated Haikou Hospital of Xiangya Medical School, Central South University, Haikou, Hainan, PR China.
Xenobiotica. 2011 Oct;41(10):844-50. doi: 10.3109/00498254.2011.589480. Epub 2011 Jun 16.
Identification of cytochrome P450 isoforms (CYPs) involved in flourofenidone (5-methyl-1-(3-fluorophenyl)-2-[1H]-pyridone, AKF-PD) 5-methylhydroxylation was carried out using human liver microsomes and cDNA-expressed human CYPs (supersomes). The experiments were performed in the following in vitro models: (A) a study of AKF-PD metabolism in liver microsomes: (a) correlations study between the rate of AKF-PD 5-methylhydroxylation and activity of CYPs; (b) the effect of specific CYPs inhibitors on the rate of AKF-PD 5-methylhydroxylation; (B) AKF-PD biotransformation by cDNA-expressed human CYPs (1A2, 2D6, 2C9, 2C19, 2E1, 3A4). In human liver microsomes, the formation of AKF-PD 5-methylhydroxylation metabolite significantly correlated with the caffeine N3-demethylase (CYP1A2), chlorzoxazone 6-hydroxylase (CYP2E1), midazolam 1'- hydroxylase (CYP3A4), tolbutamide 4-hydroxylase (CYP2C9), and debrisoquin 4-hydroxylase (CYP2D6) activities. The production of AKF-PD 5-methylhydroxylation metabolite was completely inhibited by a-naphthoflavone (a CYP1A2 inhibitor) with the IC50 value of 0.12 μM in human liver microsomes. The cDNA-expressed human CYPs generated different amounts of AKF-PD 5-methylhydroxylation metabolites, but the preference of CYP isoforms to catalyze AKF-PD metabolism was as follows: 2D6 > 2C19 > 1A2 > 2E1 > 2C9 > 3A4. The results demonstrated that CYP1A2 is the main isoform catalyzing AKF-PD 5-methylhydroxylation while CYP3A4, CYP2C9, CYP2E1, CYP2C19, and CYP2D6 are engaged to a lesser degree. Potential drug-drug interactions involving CYP1A2 may be noticed when AKF-PD is used combined with CYP1A2 inducers or inhibitors.
利用人肝微粒体和cDNA表达的人细胞色素P450同工酶（CYPs，超微粒体）鉴定参与氟非尼酮（5-甲基-1-(3-氟苯基)-2-[1H]-吡啶酮，AKF-PD）5-甲基羟基化的细胞色素P450同工酶。实验在以下体外模型中进行：（A）肝微粒体中AKF-PD代谢的研究：（a）AKF-PD 5-甲基羟基化速率与CYPs活性之间的相关性研究；（b）特定CYPs抑制剂对AKF-PD 5-甲基羟基化速率的影响；（B）cDNA表达的人CYPs（1A2、2D6、2C9、2C19、2E1、3A4）对AKF-PD的生物转化。在人肝微粒体中，AKF-PD 5-甲基羟基化代谢产物的形成与咖啡因N3-去甲基酶（CYP1A2）、氯唑沙宗6-羟化酶（CYP2E1）、咪达唑仑1'-羟化酶（CYP3A4）、甲苯磺丁脲4-羟化酶（CYP2C9）和异喹胍4-羟化酶（CYP2D6）的活性显著相关。在人肝微粒体中，α-萘黄酮（一种CYP1A2抑制剂）以0.12μM的IC50值完全抑制了AKF-PD 5-甲基羟基化代谢产物的产生。cDNA表达的人CYPs产生了不同量的AKF-PD 5-甲基羟基化代谢产物，但CYPs同工酶催化AKF-PD代谢的偏好顺序如下：2D6＞2C19＞1A2＞2E1＞2C9＞3A4。结果表明，CYP1A2是催化AKF-PD 5-甲基羟基化的主要同工酶，而CYP3A4、CYP2C9、CYP2E1、CYP2C19和CYP2D6的参与程度较低。当AKF-PD与CYP1A2诱导剂或抑制剂联合使用时，可能会注意到涉及CYP1A2的潜在药物相互作用。
