Row E, Brown S A, Stachulski A V, Lennard M S
Academic Unit of Clinical Pharmacology, University of Sheffield, Royal Hallamshire Hospital, Sheffield, S10 2JF, UK.
Drug Metab Dispos. 2006 Feb;34(2):324-30. doi: 10.1124/dmd.105.007294. Epub 2005 Nov 18.
Grapefruit juice has been found to cause an increase in the oral bioavailability of many therapeutic agents. Such interactions are believed to result from the mechanism-based inhibition of CYP3A4 activity in the intestine. Furanocoumarin dimers present in the juice have been found to be extremely potent inhibitors of CYP3A4 activity. The aim of this work was to synthesize and test a series of dimers with a view to defining the relationship between structure and inhibitory activity and establish whether they might make suitable probes of CYP3A4 activity. Eleven furanocoumarin dimers were synthesized and evaluated as inhibitors of CYP3A4 using human liver microsomes, with testosterone as the marker substrate. Four of the most potent dimers were also investigated for their effects on CYP3A4 activity in the human intestine and on five additional hepatic cytochrome P450 isoforms. The dimers showed potent dose-dependent inhibition of CYP3A4 activity in both liver and intestine; IC50 values ranged from 0.021 +/- 0.002 to 0.146 +/- 0.041 microM (mean +/- S.D. n = 3). Of the four dimers evaluated further, all showed time-dependent inhibition of CYP3A4 activity. 88Prop showed moderate inhibition of both CYP2C19 and CYP1A2 with IC50 values of 4.42 +/- 0.01 and 1.98 +/- 0.34 microM, 88Octa was found to inhibit CYP2C19 (IC50 = 3.16 +/- 0.01 microM) and 58Prop to inhibit CYP1A2 (IC50 = 2.39 +/- 0.77 microM). Minimal inhibition of CYP2D6 and CYP2C9 was observed (IC50 > 10 microM). In conclusion, all the dimers tested were extremely potent inhibitors of CYP3A4 activity. In particular, dimer 55EE was highly selective toward the enzyme, suggesting that this compound is a suitable probe for determining the contribution of CYP3A4 to drug metabolism.
已发现葡萄柚汁会使许多治疗药物的口服生物利用度增加。据信此类相互作用是由肠道中基于机制的CYP3A4活性抑制所致。已发现果汁中存在的呋喃香豆素二聚体是CYP3A4活性的极强抑制剂。这项工作的目的是合成并测试一系列二聚体，以确定结构与抑制活性之间的关系，并确定它们是否可能成为合适的CYP3A4活性探针。合成了11种呋喃香豆素二聚体，并以睾酮作为标记底物，用人肝微粒体评估其作为CYP3A4抑制剂的活性。还研究了4种最有效的二聚体对人肠道中CYP3A4活性以及另外5种肝细胞色素P450同工酶的影响。这些二聚体在肝脏和肠道中均显示出对CYP3A4活性的强效剂量依赖性抑制；IC50值范围为0.021±0.002至0.146±0.041微摩尔（平均值±标准差，n = 3）。在进一步评估的4种二聚体中，所有二聚体均显示出对CYP3A4活性的时间依赖性抑制。8,8'-Prop对CYP2C19和CYP1A2均有中度抑制作用，IC50值分别为4.42±0.01和1.98±0.34微摩尔，发现8,8'-Octa抑制CYP2C19（IC50 = 3.16±0.01微摩尔），5,8'-Prop抑制CYP1A2（IC50 = 2.39±0.77微摩尔）。观察到对CYP2D6和CYP2C9的抑制作用极小（IC50> 10微摩尔）。总之，所有测试的二聚体都是CYP3A4活性的极强抑制剂。特别是，二聚体5,5'-EE对该酶具有高度选择性，表明该化合物是确定CYP3A4对药物代谢贡献的合适探针。
