2005 Fiscal Year Final Research Report Summary
Structural analysis of substrate binding region in carboxylesterase and design of ester-containing drug
| Project/Area Number |
16590085
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Kumamoto University |
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Principal Investigator |
IMAI Teruko Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Professor, 大学院・医学薬学研究部, 教授 (70176478)
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| Co-Investigator(Kenkyū-buntansha) |
HASHIMOTO Mitsuru Kumamoto University, Assistant professor, 大学院・医学薬学研究部, 助手 (80359968)
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| Project Period (FY) |
2004 – 2005
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| Keywords | carboxylesterase / hydrolysis / drug disposition / intestinal absorption / substrate specificity / prodrug / molecular design / acyltranslation |
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| Research Abstract |
The objective of this research is the establishment of successful design of ester-containing drug such as prodrug based on substrate specificity of carboxylesterases, a serine esterase. Human carboxylesterase 1 (hCE-1) and carboxylesterase 2 (hCE-2) are present in several organs, the hydrolase activity in liver and small intestine is predominantly attributed to hCE-1 and hCE-2, respectively. The substrate specificities of hCE-1 and hCE-2 were significantly different. hCE-1 mainly hydrolyzed substrates with small alcohol and large acyl groups, however its wide active pocket sometimes allowed it to act on structurally distinct compounds containing either large or small alcohol moieties. In contrast, hCE-2 recognized substrates with large alcohol and small acyl groups, and its substrate specificity might be restricted by acyl-hCE-2 conjugate formation due to conformational interference around the active pocket. Furthermore, hCE-1 showed high transacylation activity, especially with hydrop
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hobic alcohols, whereas this was negligible for hCE-2. Transacylation has been proposed as a possible reason for low hydrolysis by hCE-1 of substrates with hydrophobic alcohol groups, as transacylation can progress at the same time when a compound is hydrolyzed by hCE-1.
The extensive intestinal hydrolysis ability by CES during drug absorption was determined by rat in situ single-pass perfusion. CES contributed around 80% of hydrolysis in the small intestine. Since hydrolyzed products were present at higher concentration in the epithelial cells rather than blood vessel and intestinal lumen, hydrolysates were transported by specific efflux transporter and passive diffusion according to pH-partition.
We could design the successful prodrug of fexofenadine, a large acyl compound, by considering hydrolase activity of hCE1 and hCE2. The further detailed substrate specificity for CES alongside development of in vitro evaluation systems for absorption of compounds and their hydrolysates will help us to design the ideal prodrug. Less
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