Photochemmically Stabilized Formulation of Dacarbazine with Reduced Production of Algogenic Photodegradants
Photochemmically Stabilized Formulation of Dacarbazine with Reduced Production of Algogenic Photodegradants
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减少致藻光降解剂产生的达卡巴嗪光化学稳定制剂
DOI：
10.1016/j.ijpharm.2019.04.063
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发表时间：
2019
影响因子：
5.8
通讯作者：
T. Oguchi
中科院分区：
文献类型：
--
作者：
A. Uchida;H. Ohtake;Y. Suzuki;H. Sato;Y. Seto;S. Onoue;T. Oguchi
本研究旨在开发一种光化学稳定的达卡巴嗪制剂[5-（3,3-二甲基-1-三氮基）咪唑-4-羧酰胺]；DTIC]用于减少致藻光降解物（5-重氮咪唑-4-羧酰胺；重氮- ic）的产生。通过紫外-可见光光谱分析、活性氧（ROS）测定和光稳定性测试对DTIC的光化学性质进行了表征。大鼠静脉给药DTIC制剂（1 mg-DTIC/kg）后进行药代动力学研究。DTIC在UVA范围内表现出较强的吸收，光照后的DTIC表现出明显的ROS生成。因此，DTIC具有较高的光反应电位。将DTIC（1 mM）暴露在模拟阳光（250 W/m2）下3 min后，估计剩余的DTIC和生成的Diazo-IC分别约为230 μM和600 μM。在DTIC（1 mM）中加入l-抗坏血酸、l-半胱氨酸（Cys）、l-组氨酸、d -甘尼醇、l-色氨酸、orl-酪氨酸等自由基清除剂（1 mM）可减弱DTIC光反应，其中Cys对DTIC光降解和重氮- ic光生成的抑制作用分别为34%和86%。DTIC与含Cys的DTIC计算药动学参数差异无统计学意义（0.67 mg/kg）。综上所述，Cys的补充使用将是提高DTIC光稳定性的有效途径，同时减少重氮- ic的产生。
The present study aimed to develop a photochemically stabilized formulation of dacarbazine [5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide; DTIC] for reducing the production of algogenic photodegradant (5-diazoimidazole-4-carboxamide; Diazo-IC). Photochemical properties of DTIC were characterized by UV-visible light spectral analysis, reactive oxygen species (ROS) assay, and photostability testing. A pharmacokinetic study was conducted after intravenous administration of DTIC formulations (1 mg-DTIC/kg) to rats. DTIC exhibited strong absorption in the UVA range, and photoirradiated DTIC exhibited marked ROS generation. Thus, DTIC had high photoreactive potential. After exposure of DTIC (1 mM) to simulated sunlight (250 W/m2) for 3 min, remaining DTIC and yielded Diazo-IC were estimated to be ca. 230 μM and 600 μM, respectively. The addition of radical scavenger (1 mM), includingl-ascorbic acid,l-cysteine (Cys),l-histidine, D-mannitol,l-tryptophan, orl-tyrosine, to DTIC (1 mM) could attenuate DTIC photoreactions, and in particular, the addition of Cys to DTIC brought ca. 34% and 86% inhibition of DTIC photodegradation and Diazo-IC photogeneration, respectively. There were no significant differences in the calculated pharmacokinetic parameters of DTIC between DTIC and DTIC with Cys (0.67 mg/kg). From these findings, the supplementary use of Cys would be an effective approach to improve the photostability of DTIC with less production of Diazo-IC.