Binkhathlan Ziyad
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Drug Res (Stuttg). 2017 Oct;67(10):591-595. doi: 10.1055/s-0043-111411. Epub 2017 Jun 19.
Cremophor EL is a nonionic surfactant widely used in pharmaceutical formulations. Nonetheless, there are several reports on the influence of this excipient on the protein binding, pharmacokinetics, and pharmacodynamics of drugs. Valspodar is an investigational non-immunosuppressive derivative of cyclosporine A, used in clinical trials for treatment of multidrug resistant tumors. The formulation of valspodar (Amdray) contains cremophor EL and ethanol as solubilizing agents. The main aim of the current study was to assess the plasma protein binding (in vitro) and the pharmacokinetic profile of valspodar in the cremophor EL-based formulation in comparison to a cremophor EL-free formulation following intravenous (i. v.) administration to rats. Valspodar dissolved in PEG 400/ethanol (diluted in Dextrose 5%) was used as the cremophor EL-free formulation. The in vitro plasma unbound fraction (f ) of valspodar in the cremophor EL formulation was 2.3-fold higher than the PEG 400/ethanol formulation. Following a single i. v. dose of 5 mg/kg, valspodar in the cremophor EL-based formulation had around 50% lower plasma AUC compared to the PEG 400/ethanol formulation. Moreover, the cremophor EL formulation had significantly higher volume of distribution and clearance in comparison to the PEG 400-based formulation. The results highlight the significance of excipient-drug interaction that should not be overlooked during the early stages of drug development.
聚氧乙烯蓖麻油（Cremophor EL）是一种广泛应用于药物制剂的非离子表面活性剂。尽管如此，关于这种辅料对药物蛋白结合、药代动力学和药效学影响的报道已有不少。伐司朴达是环孢素A的一种研究性非免疫抑制衍生物，用于多药耐药肿瘤治疗的临床试验。伐司朴达（Amdray）制剂含有聚氧乙烯蓖麻油（Cremophor EL）和乙醇作为增溶剂。本研究的主要目的是评估静脉注射给大鼠后，与不含聚氧乙烯蓖麻油（Cremophor EL）的制剂相比，基于聚氧乙烯蓖麻油（Cremophor EL）的伐司朴达制剂的血浆蛋白结合（体外）和药代动力学特征。溶解于聚乙二醇400/乙醇（用5%葡萄糖稀释）中的伐司朴达用作不含聚氧乙烯蓖麻油（Cremophor EL）的制剂。伐司朴达在聚氧乙烯蓖麻油（Cremophor EL）制剂中的体外血浆未结合分数（f）比聚乙二醇400/乙醇制剂高2.3倍。单次静脉注射剂量为5mg/kg后，基于聚氧乙烯蓖麻油（Cremophor EL）的伐司朴达制剂的血浆AUC比聚乙二醇400/乙醇制剂低约50%。此外，与基于聚乙二醇400的制剂相比，聚氧乙烯蓖麻油（Cremophor EL）制剂的分布容积和清除率显著更高。结果突出了辅料 - 药物相互作用的重要性，在药物研发早期不应被忽视。
