Weiss Johanna, Haefeli Walter Emil
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Drug Metab Dispos. 2006 Feb;34(2):203-7. doi: 10.1124/dmd.105.007377. Epub 2005 Nov 4.
In cell culture systems with aqueous buffers, concentration-response curves to lipophilic inhibitors are difficult to establish because plateau effects (Imax) are often not reached because of limited drug solubility. Consequently, the inhibitory potency of a compound will not be definable using IC50 values (concentration exerting 50% of Imax). Since alternative potency measures f2 values, the concentrations required to double baseline signals have been proposed. Using both methods, we reevaluated the concentration-response curves of calcein assays with 78 compounds in three different cell culture systems and found a close correlation between both methods (r(s) = 0.93-0.99, p < or = 0.0028). These findings suggest that f2 values are a valuable alternative to define rank orders of highly lipophilic inhibitors as a basis for the prediction of pharmacological interaction properties in clinical settings. Although it was only tested for inhibition of P-glycoprotein, it seems likely that this method may be transferred to other assays with other proteins.
在使用水性缓冲液的细胞培养系统中，由于药物溶解度有限，常常无法达到平台效应（Imax），因此难以建立亲脂性抑制剂的浓度-效应曲线。所以，无法使用IC50值（达到Imax的50%时的浓度）来定义化合物的抑制效力。由于替代效力测量方法f2值（使基线信号加倍所需的浓度）已被提出。我们使用这两种方法，在三种不同的细胞培养系统中重新评估了78种化合物的钙黄绿素检测的浓度-效应曲线，发现两种方法之间存在密切相关性（r(s) = 0.93 - 0.99，p ≤ 0.0028）。这些发现表明，f2值是定义高亲脂性抑制剂排名顺序的一种有价值的替代方法，可作为预测临床环境中药理学相互作用特性的基础。尽管仅针对P-糖蛋白抑制进行了测试，但这种方法似乎有可能应用于其他蛋白质的其他检测。
