Use of solubilizers in preclinical formulations: Effect of Cremophor EL on the pharmacokinetic properties on early discovery compounds

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• 作者：Bo Liu ; ^{bliu@gnf.org" class="auth_mail" title="E-mail the corresponding author} ; William Perry Gordon ; Wendy Richmond ; Todd Groessl ; Tove Tuntland
• 关键词：Cremophor EL ; Surfactant ; Formulation ; Pharmacokinetics
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：25 May 2016
• 年：2016
• 卷：87
• 期：Complete
• 页码：52-57
• 全文大小：628 K

文摘

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 (V_ss) and plasma clearance (CL) were observed in compounds with moderate to high V_ss or CL. The plasma V_ss decreased more than 2-fold and the V_ss binning category decreased by one unit (e.g. from moderate to low V_ss) 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 (T_1/2) 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 V_ss. Taken together, these findings indicated that Cremophor EL altered the intrinsic PK properties of these discovery compounds in a concentration dependent manner.