Greenblatt David J, Zhao Yanli, Hanley Michael J, Chen Chunxian, Harmatz Jerold S, Cancalon Paul F, Gmitter Frederick G
Sackler Program in Pharmacology and Experimental Therapeutics, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical Center, Boston, MA 02111, USA.
Xenobiotica. 2012 Dec;42(12):1163-9. doi: 10.3109/00498254.2012.700428. Epub 2012 Jul 18.
A citrus breeding program aimed at developing low furanocoumarin (FC) grapefruit cultivars provided 40 grapefruit juice (GFJ) samples containing variable concentrations of FC derivatives, established as being mechanism-based (irreversible) inhibitors of human CYP3A isoforms. The principal inhibitory FCs were identified as 6',7'-dihydroxybergamottin, along with a series of dimeric compounds (spiroesters) having high inhibitory potency. A random subset of the GFJ samples (n = 25) were tested as CYP3A inhibitors using an in vitro model based on human liver microsomal metabolism of the index substrate triazolam. The reciprocal values of in vitro 50% inhibitory concentrations (IC(50)) were highly correlated with concentrations of inhibitory FCs in the GFJ samples (r(2) = 0.96). However the correlations were driven mainly by a few samples having high FC content and high reciprocal IC(50) (corresponding to low IC(50)). Among the rest of the samples, the relationship was less robust. Further study is needed to determine how low the FC content needs to be (or how high the IC(50) needs to be) to assure minimal risk of clinical interactions involving GFJ and CYP3A substrate drugs.
一个旨在培育低呋喃香豆素（FC）葡萄柚品种的柑橘育种项目提供了40个葡萄柚汁（GFJ）样本，这些样本含有浓度各异的FC衍生物，已确定其为人类CYP3A亚型的基于机制（不可逆）的抑制剂。主要的抑制性FC被鉴定为6',7'-二羟基佛手柑内酯，以及一系列具有高抑制效力的二聚体化合物（螺环酯）。使用基于指数底物三唑仑的人肝微粒体代谢的体外模型，对GFJ样本的一个随机子集（n = 25）进行了CYP3A抑制剂测试。体外50%抑制浓度（IC(50)）的倒数与GFJ样本中抑制性FC的浓度高度相关（r(2) = 0.96）。然而，这种相关性主要由少数FC含量高且倒数IC(50)高（对应低IC(50)）的样本驱动。在其余样本中，这种关系不那么稳固。需要进一步研究来确定FC含量需要多低（或IC(50)需要多高），以确保涉及GFJ和CYP3A底物药物的临床相互作用风险最小。
