DP7, a novel dihydropyridine multidrug resistance reverter, shows only weak inhibitory activity on human CYP3A enzyme(s)
DP7, a novel dihydropyridine multidrug resistance reverter, shows only weak inhibitory activity on human CYP3A enzyme(s)
复制标题
DOI：
10.1016/j.ejphar.2009.04.019
复制
发表时间：
2009-07-01
影响因子：
5
通讯作者：
Valoti, Massimo
中科院分区：
文献类型：
--
作者：
D'Elia, Paolo;De Matteis, Francesco;Valoti, Massimo
本研究的目的是研究 3,5-二苯甲酰基-4-(3-苯氧基-苯基)-1,4-二氢-2,6-二甲基吡啶 (DP7)（一种新型多药耐药性 (MDR) 回复剂）对人和大鼠肝微粒体细胞色素 P450 (CYP) 活性的影响。使用选择性底物（CYP 活性标记物）评估 DP7 的效果。对于大鼠微粒体，使用乙氧基试卤灵 (ETR) 作为 CYP1A1 的底物，使用戊氧基试卤灵 (PTR) 作为 2B 的底物，使用苄氧基试卤灵 (BZR) 作为 1A1/2、2B、2C、3A 的底物。使用 7-苄氧基喹啉 (BQ) 或 [3-[3(3,4-二氟苄基)氧基]-5,5-二甲基-4-[4-(甲磺酰基)-苯基]呋喃-2-(5H)-酮] (DFB) 通过荧光法评估大鼠 (3A2) 和人 (3A4) 肝微粒体的 CYP3A 酶活性。当大鼠微粒体与DP7一起孵育时，获得浓度-抑制曲线。 DP7抑制使PTR的IC50值为3.8μM，ETR为3.8μM，BZR为10.4μM，并且本质上不具有竞争性；而且，它们是可逆的。当BQ用作大鼠微粒体的底物时，DP7抑制其氧化，IC50值为4.17μM，而在人微粒体中使用最高DP7浓度（75μM）时，这种氧化仅被抑制25％。相反，当使用DFB作为底物时，DP7与任一物种的微粒体制剂显示出相同的IC50值(34.67μM)。 DP7 对大鼠肝微粒体 CYP 亚型的中度抑制和对人类 CYP3A4 酶活性的弱抑制表明 DP7 在人体中不会产生重要的、不可预测的药代动力学相互作用。这一结论支持了该化合物作为开发具有治疗意义的新型 MDR 逆转二氢吡啶的先导作用 (C) 2009 Elsevier B.V. 保留所有权利。
The aim of this study was to investigate the effects of 3,5-dibenzoyl-4-(3-phenoxy-phenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), a novel multidrug resistance (MDR) reverter, on cytochrome P450 (CYP)-activities by human and rat liver microsomes. Effects of DP7 were assessed with use of selective substrates, markers of CYP activities. With rat microsomes, ethoxyresorufin (ETR) was used as substrate for CYP1A1, penthoxyresorufin (PTR) for 2B, benzyloxyresorufin (BZR) for 1A1/2, 2B, 2C, 3A. CYP3A enzyme activities of rat (3A2) and human (3A4) liver microsomes, were assessed fluorimetrically using either 7-benzyloxy-quinoline (BQ) or [3-[3(3,4-difluorobenzyl)oxy]-5,5-dimethyl-4-[4-(methylsulfonyl)-phenyl]furan-2-(5H)-one] (DFB). When rat microsomes were incubated with DP7, concentration-inhibition curves were obtained. DP7 inhibitions gave IC50 values of 3.8 mu M for PTR, 3.8 mu M for ETR and 10.4 mu M for BZR and were not competitive in nature; moreover, they were reversible. When BQ was used as substrate of rat microsomes, DP7 inhibited its oxidation with an IC50 value of 4.17 mu M while this oxidation was inhibited by only 25% at the highest DP7 concentration used (75 mu M) with human microsomes. On the contrary, when DFB was used as substrate, DP7 showed identical IC50 values (34.67 mu M) with microsomal preparations from either species. The moderate inhibition of CYP isoforms of rat liver microsomes and the weak inhibition of human CYP3A4 enzyme activity operated by DP7, suggest that DP7 in man should not give rise to important, unpredictable pharmacokinetic interactions. This conclusion supports the role of this compound as a lead for the development of novel MDR reverterting dihydropyridines of therapeutic interest (C) 2009 Elsevier B.V. All rights reserved.