Design, synthesis and biological evaluation of water-soluble phenytoin prodrugs considering the substrate recognition ability of human carboxylesterase 1

被引：6

作者：

Takahashi, Masato ^{[1
]}

Lee, Yeon Joo ^{[1
]}

Kanayama, Teruhiko ^{[1
]}

Kondo, Yusuke ^{[1
]}

Nishio, Kazuki ^{[1
]}

Mukai, Kota ^{[1
]}

Haba, Masami ^{[1
]}

Hosokawa, Masakiyo ^{[1
]}

机构：

[1] Chiba Inst Sci, Fac Pharm, 15-8 Shiorni Cho, Choshi, Chiba 2880025, Japan

来源：

EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES | 2020年 / 152卷

关键词：

Prodrug; Water-soluble; Carboxylesterase; Phenytoin; Substrate; Specificity; METABOLIC-ACTIVATION; HUMAN LIVER; ESTER; AGENT; RAT;

D O I：

10.1016/j.ejps.2020.105455

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Human carboxylesterase 1 (hCES1) is a hydrolase that is mainly expressed in the liver and lung and plays the most important role in the metabolic activation of ester-type prodrugs. In this study, design, synthesis and evaluation of water-soluble phenytoin prodrugs were performed with consideration of the substrate recognition ability of hCES1. The phenytoin prodrugs were synthesized in two steps without column chromatography. It was confirmed that all prodrugs are efficiently converted to phenytoin in a human liver microsome (HLM) solution (up to 54.6 nmol/mg protein/min). Although some of the prodrugs were degraded in strongly basic solution, the solubility of all prodrugs was greater than that of phenytoin in buffer solutions at pH 7.4 and 8.3. Among the synthesized phenytoin prodrugs, the 3,3-dimethylglutarate prodrug was superior in terms of solubility and stability, and it showed solubility of 10 mg/mL or more (phenytoin: <0.1 mg/mL) in a solution of pH 8.3. It was also found that the 3,3-dimethylglutarate prodrug was selectively activated by hCES1 but not hCES2 or arylacetamidodeacetylase.

引用

页数：8