Modulating the solubility and pharmacokinetic properties of 5-fluorouracil via cocrystallization
Modulating the solubility and pharmacokinetic properties of 5-fluorouracil via cocrystallization
复制标题
调节溶解度和药代动力学
DOI：
10.1039/d0ce00409j
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发表时间：
2020-06-07
期刊：
影响因子：
3.1
通讯作者：
Chen, Jia-Mei
中科院分区：
文献类型：
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作者：
Dai, Xia-Lin;Wu, Chao;Chen, Jia-Mei
5-氟尿嘧啶(5FU)是一种经典的抗代谢药物，具有广谱的抗肿瘤作用。然而，5FU口服吸收不完全，生物半衰期短，峰谷现象明显，给药要求频繁，副作用严重。本论文采用基于晶体工程的药物共结晶方法，通过改变5FU的水溶性来调节其药代动力学性质。合成了四种5FU与一组二羟基苯甲酸的共晶体，并对其结构进行了表征。粉末溶解实验表明，与纯5FU相比，所有共晶均表现出不同的水溶度和溶解速率。与纯5FU相比，两种共晶的表观溶解度分别提高了34%和11%，而另外两种共晶的表观溶解度分别降低了27%和51%。在体内药代动力学研究中，所有共晶体的药代动力学参数，包括C-max、t(Max)、MRT0-t、t(1/2)和AUC(0-t)以及药动学曲线的形状都发生了相应的变化。本研究对于利用共结晶技术调节口服吸收不良药物的药代动力学性质，特别是在临床实践中避免体内峰谷效应，减少副作用具有重要意义。
5-Fluorouracil (5FU) is a classical anti-metabolic drug with broad-spectrum antitumor effects. However, the oral absorption of 5FU is incomplete with a short biological half-life and an obvious peak-valley phenomenon, leading to the frequent administration requirement and severe side effects. Herein, a pharmaceutical cocrystallization approach based on crystal engineering was employed to modulate the pharmacokinetic properties of 5FU by changing its aqueous solubility. Four cocrystals of 5FU with a group of dihydroxybenzoic acids were synthesized and characterized. The powder dissolution experiments showed that all the cocrystals exhibited different aqueous solubilities and dissolution rates in comparison with pure 5FU. As compared to pure 5FU, the apparent solubility values of two cocrystals were increased by 34% and 11% while those of the other two cocrystals were reduced by 27% and 51%, respectively. The pharmacokinetic parameters of all the cocrystals, including C-max, t(max), MRT0-t, t(1/2) and AUC(0-t), as well as the shape of the pharmacokinetic curves, were accordingly altered in the in vivo pharmacokinetic study. This study has important implications for using cocrystallization techniques to modulate the pharmacokinetic properties of drugs with undesirable oral absorption, especially to avoid the in vivo peak-valley effect and reduce side effects in clinical practice.