Liu Bo, Gordon William Perry, Richmond Wendy, Groessl Todd, Tuntland Tove
Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation (GNF), Novartis Institute of Biomedical Research (NIBR), San Diego, CA, USA.
Metabolism and Pharmacokinetics, Genomics Institute of the Novartis Research Foundation (GNF), Novartis Institute of Biomedical Research (NIBR), San Diego, CA, USA.
Eur J Pharm Sci. 2016 May 25;87:52-7. doi: 10.1016/j.ejps.2015.10.015. Epub 2015 Oct 20.
The aim of the present study was to determine whether Cremophor EL is a suitable surfactant that can be routinely applied to pharmacokinetic (PK) studies in early drug discovery without influencing the intrinsic PK characteristics of the new chemical entities (NCEs). Cremophor EL, a polyoxyl 35 castor oil, has been used as a solubilization aid for water-insoluble compounds in pre-clinical drug discovery. The effect of Cremophor EL on the PK properties of NCEs was examined in seven structurally diverse discovery compounds after intravenous administration. Significant effects of Cremophor EL on plasma volume of distribution (Vss) and plasma clearance (CL) were observed in compounds with moderate to high Vss or CL. The plasma Vss decreased more than 2-fold and the Vss binning category decreased by one unit (e.g. from moderate to low Vss) in 6 of 7 test compounds. Two to five-fold reduction of CL was observed with these 6 compounds. Effect on the terminal half-life (T1/2) was minimal. Using one of these 7 NCEs, concentration dependent effect of Cremophor EL in the vehicle was also determined. Higher percentage of Cremophor EL in vehicle resulted in progressively increased alterations on the plasma CL and Vss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner.
本研究的目的是确定聚氧乙烯蓖麻油（Cremophor EL）是否为一种合适的表面活性剂，可在药物早期研发的药代动力学（PK）研究中常规应用，而不影响新化学实体（NCEs）的内在PK特性。聚氧乙烯蓖麻油（Cremophor EL），一种聚氧乙烯35蓖麻油，已在临床前药物研发中用作水不溶性化合物的助溶剂。静脉给药后，在7种结构不同的研发化合物中研究了聚氧乙烯蓖麻油（Cremophor EL）对NCEs PK特性的影响。在具有中度至高分布容积（Vss）或血浆清除率（CL）的化合物中，观察到聚氧乙烯蓖麻油（Cremophor EL）对血浆分布容积（Vss）和血浆清除率（CL）有显著影响。在7种测试化合物中的6种中，血浆Vss下降超过2倍，Vss分类降低一个单位（例如从中度降至低Vss）。这6种化合物的CL降低了2至5倍。对末端半衰期（T1/2）的影响最小。使用这7种NCEs中的一种，还确定了聚氧乙烯蓖麻油（Cremophor EL）在溶媒中的浓度依赖性效应。溶媒中聚氧乙烯蓖麻油（Cremophor EL）的百分比越高，对血浆CL和Vss的改变就越大。综上所述，这些发现表明聚氧乙烯蓖麻油（Cremophor EL）以浓度依赖的方式改变了这些研发化合物的内在PK特性。
