Martin Philip, Giardiello Marco, McDonald Tom O, Rannard Steven P, Owen Andrew
Department of Molecular and Clinical Pharmacology, University of Liverpool, Block H, 70 Pembroke Place, Liverpool, L69 3GF, U.K.
Mol Pharm. 2013 Jul 1;10(7):2739-48. doi: 10.1021/mp400175n. Epub 2013 Jun 10.
Polymers and surfactants are commonly used as excipients in oral formulations and are generally considered to be inert. However, relatively few studies have assessed their interaction with enzymes involved in the absorption, distribution, metabolism, and elimination of drugs. We have investigated the impact of twenty-three commonly used excipients (ten polymers and thirteen surfactants) on seven cytochrome P450 (CYP450) isoforms using baculosome-derived CYP450 enzymes across a range of concentrations. Time-course fluorescent readings were then taken to generate IC50 (inhibition) or EC50 (activation) values for excipient effects on CYP450 activity. All excipients had an observable effect activity of at least one CYP450 isoform with the majority of excipients altering substrate metabolism of at least 57% of CYP450s studied. In addition, most excipients were capable of inhibiting and increasing activity of several different CYP450 isoforms. Although the majority of these effects required concentrations outside those achievable therapeutically (>100 μM), almost 20% were seen at concentrations below 100 μM, and these results indicate that several excipients have the potential to modify the pharmacokinetics of administered drugs.
聚合物和表面活性剂通常用作口服制剂中的辅料，一般被认为是惰性的。然而，相对较少的研究评估过它们与参与药物吸收、分布、代谢和消除的酶之间的相互作用。我们使用杆状病毒体衍生的细胞色素P450（CYP450）酶，在一系列浓度下研究了23种常用辅料（10种聚合物和13种表面活性剂）对7种CYP450同工酶的影响。然后进行时间进程荧光读数，以生成辅料对CYP450活性影响的IC50（抑制）或EC50（激活）值。所有辅料对至少一种CYP450同工酶都有可观察到的效应活性，大多数辅料改变了所研究的至少57%的CYP450的底物代谢。此外，大多数辅料能够抑制和增加几种不同CYP450同工酶的活性。虽然这些效应中的大多数需要高于治疗可达到的浓度（>100μM），但在低于100μM的浓度下也观察到了近20%的效应，这些结果表明几种辅料有可能改变给药药物的药代动力学。
