Department of Pharmacy, the First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China.
Department of Pharmacy, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China.
Mol Pharm. 2023 Sep 4;20(9):4517-4527. doi: 10.1021/acs.molpharmaceut.3c00213. Epub 2023 Aug 1.
This study is designed to compare drug encapsulation by cucurbit[7]uril and β-cyclodextrin, using fluorofenidone as a model drug. Single-crystal X-ray diffraction analysis was employed to successfully determine the crystal structures of fluorofenidone·H@cucurbit[7]uril Form, fluorofenidone@cucurbit[7]uril Form, and fluorofenidone@β-cyclodextrin Form. Keto-enol tautomerization of fluorofenidone mediated by cucurbit[7]uril in acid solution is confirmed by crystal structures, pH titration, and nuclear magnetic resonance experiments. However, β-cyclodextrin cannot cause the keto-enol tautomerization of fluorofenidone under similar conditions. The phase solubility study demonstrates that cucurbit[7]uril has a much higher solubilization capacity for fluorofenidone than β-cyclodextrin in 0.1 M HCl since the values of fluorofenidone with cucurbit[7]uril and β-cyclodextrin were 1223.97 ± 452.68 and 78.49 ± 10.56 M, respectively. Excellent solubility can be attributed to the keto-enol tautomerization of fluorofenidone under the conditions of cucurbit[7]uril in acid solution. The enol form of fluorofenidone is encapsulated by cucurbit[7]uril by hydrogen bonding interaction and hydrophobic interaction to increase binding affinity. Rat pharmacokinetic studies demonstrate that the area under the plasma concentration-time curve from time 0 to 7 h value of fluorofenidone@cucurbit[7]uril complex is 1.70-fold greater than that of free fluorofenidone, and the mean residence time from time 0 to 7 h is slightly prolonged from 1.29 to 1.76 h ( < 0.01) after oral administration. However, no significant difference is found between fluorofenidone and fluorofenidone@β-cyclodextrin complex. This work indicates that the induction of keto-enol tautomerization of drugs using macrocyclic molecules has the potential to be an effective method to improve their solubility and bioavailability, providing valuable insights for the application of macrocyclic molecules in the biomedical field.
这项研究旨在比较葫芦[7]脲和β-环糊精对药物的包封作用，以氟苯嘧啶酮为模型药物。采用单晶 X 射线衍射分析成功确定了氟苯嘧啶酮·H@葫芦[7]脲形式、氟苯嘧啶酮@葫芦[7]脲形式和氟苯嘧啶酮@β-环糊精形式的晶体结构。通过晶体结构、pH 滴定和核磁共振实验证实，在酸性溶液中，葫芦[7]脲介导的氟苯嘧啶酮发生酮-烯醇互变异构。然而，在类似条件下，β-环糊精不能引起氟苯嘧啶酮的酮-烯醇互变异构。相溶解度研究表明，在 0.1 M HCl 中，葫芦[7]脲对氟苯嘧啶酮的增溶能力比β-环糊精高得多，因为氟苯嘧啶酮与葫芦[7]脲和β-环糊精的 值分别为 1223.97±452.68 和 78.49±10.56 M。良好的溶解度可归因于酸性溶液中葫芦[7]脲条件下氟苯嘧啶酮的酮-烯醇互变异构。氟苯嘧啶酮的烯醇形式通过氢键相互作用和疏水相互作用被葫芦[7]脲包封，从而增加结合亲和力。大鼠药代动力学研究表明，氟苯嘧啶酮@葫芦[7]脲复合物的 0 至 7 h 时血浆浓度-时间曲线下面积值是游离氟苯嘧啶酮的 1.70 倍，口服后 0 至 7 h 的平均驻留时间从 1.29 略微延长至 1.76 h（ < 0.01）。然而，氟苯嘧啶酮与氟苯嘧啶酮@β-环糊精复合物之间没有发现显著差异。这项工作表明，使用大环分子诱导药物的酮-烯醇互变异构有可能成为提高其溶解度和生物利用度的有效方法，为大环分子在生物医学领域的应用提供了有价值的见解。
