Synthesis and evaluation of haloperidol ester prodrugs metabolically activated by human carboxylesterase
Two types of haloperidol prodrugs in which a chemical modification was carried out on the hydroxyl group or carbonyl group were synthesized, and their metabolic activation abilities were evaluated in a human liver microsome (HLM) solution, a human small intestine microsome (HIM) solution and solutio...
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| Veröffentlicht in: | European journal of pharmaceutical sciences 2019-04, Vol.132, p.125-131 |
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| container_title | European journal of pharmaceutical sciences |
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| creator | Takahashi, Masato Uehara, Tomoki Nonaka, Minori Minagawa, Yuka Yamazaki, Riona Haba, Masami Hosokawa, Masakiyo |
| description | Two types of haloperidol prodrugs in which a chemical modification was carried out on the hydroxyl group or carbonyl group were synthesized, and their metabolic activation abilities were evaluated in a human liver microsome (HLM) solution, a human small intestine microsome (HIM) solution and solutions of human recombinant carboxylesterases (hCESs). The metabolic activation rates of alcohol ester prodrugs in HLM solution were similar to those in hCES2 solution, and haloperidol pentanoate and haloperidol hexanoate showed high metabolic activation rates in the synthesized alcohol ester prodrugs. In addition, haloperidol acetate and haloperidol 2-methylbutanoate were hydrolyzed as slowly as haloperidol decanoate. The results suggested that haloperidol prodrugs with a small chain or a branched chain are useful as prodrugs for sustained release. The metabolic activation rate of the enol ester prodrug in HLM solution was similar to that in hCES1 solution, and the enol ester prodrug was found to behave differently from alcohol ester prodrugs, which were metabolically activated by hCES2.
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| doi_str_mv | 10.1016/j.ejps.2019.03.009 |
| format | Article |
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[Display omitted]</description><subject>Carboxylesterase</subject><subject>Enol ester</subject><subject>Haloperidol</subject><subject>Prodrug</subject><subject>Sustained release</subject><issn>0928-0987</issn><issn>1879-0720</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNp9kMuO1DAQRS0EYpoZfoAF8pJNQtl52JbYoBEvaaRZDLO2_KjQbjlxYyct8vek6YElq9qce6vqEPKGQc2A9e8PNR6OpebAVA1NDaCekR2TQlUgODwnO1BcVqCkuCKvSjkAQC8FvCRXDUghGwk7sn9Yp3mPJRRqJk_xZOJi5pAmmga6NzEdMQefIsUyY6bHnHxefhQ64mxsisGZGFdq3BxOZkZP7Ur3y2gm6ky26dca_-RMwRvyYjCx4OuneU0eP3_6fvu1urv_8u32413lWs7nyrTMettz4H4waLyzrVDoeMd6VF42Q2cRWds6cELwXnbYdUJaVK1vgBnXXJN3l97t1J_Ltl2PoTiM0UyYlqI5U00PXDG-ofyCupxKyTjoYw6jyatmoM-G9UGfDeuzYQ2N3gxvobdP_Ysd0f-L_FW6AR8uAG5fngJmXVzAyaEPGd2sfQr_6_8NfJOQGA</recordid><startdate>20190430</startdate><enddate>20190430</enddate><creator>Takahashi, Masato</creator><creator>Uehara, Tomoki</creator><creator>Nonaka, Minori</creator><creator>Minagawa, Yuka</creator><creator>Yamazaki, Riona</creator><creator>Haba, Masami</creator><creator>Hosokawa, Masakiyo</creator><general>Elsevier B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0003-3233-6783</orcidid></search><sort><creationdate>20190430</creationdate><title>Synthesis and evaluation of haloperidol ester prodrugs metabolically activated by human carboxylesterase</title><author>Takahashi, Masato ; Uehara, Tomoki ; Nonaka, Minori ; Minagawa, Yuka ; Yamazaki, Riona ; Haba, Masami ; Hosokawa, Masakiyo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c422t-a41bdb6202dfaeadcb479ec2516e9d83f5bee144c0c772685e5578be94d301ac3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Carboxylesterase</topic><topic>Enol ester</topic><topic>Haloperidol</topic><topic>Prodrug</topic><topic>Sustained release</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takahashi, Masato</creatorcontrib><creatorcontrib>Uehara, Tomoki</creatorcontrib><creatorcontrib>Nonaka, Minori</creatorcontrib><creatorcontrib>Minagawa, Yuka</creatorcontrib><creatorcontrib>Yamazaki, Riona</creatorcontrib><creatorcontrib>Haba, Masami</creatorcontrib><creatorcontrib>Hosokawa, Masakiyo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takahashi, Masato</au><au>Uehara, Tomoki</au><au>Nonaka, Minori</au><au>Minagawa, Yuka</au><au>Yamazaki, Riona</au><au>Haba, Masami</au><au>Hosokawa, Masakiyo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and evaluation of haloperidol ester prodrugs metabolically activated by human carboxylesterase</atitle><jtitle>European journal of pharmaceutical sciences</jtitle><addtitle>Eur J Pharm Sci</addtitle><date>2019-04-30</date><risdate>2019</risdate><volume>132</volume><spage>125</spage><epage>131</epage><pages>125-131</pages><issn>0928-0987</issn><eissn>1879-0720</eissn><abstract>Two types of haloperidol prodrugs in which a chemical modification was carried out on the hydroxyl group or carbonyl group were synthesized, and their metabolic activation abilities were evaluated in a human liver microsome (HLM) solution, a human small intestine microsome (HIM) solution and solutions of human recombinant carboxylesterases (hCESs). The metabolic activation rates of alcohol ester prodrugs in HLM solution were similar to those in hCES2 solution, and haloperidol pentanoate and haloperidol hexanoate showed high metabolic activation rates in the synthesized alcohol ester prodrugs. In addition, haloperidol acetate and haloperidol 2-methylbutanoate were hydrolyzed as slowly as haloperidol decanoate. The results suggested that haloperidol prodrugs with a small chain or a branched chain are useful as prodrugs for sustained release. The metabolic activation rate of the enol ester prodrug in HLM solution was similar to that in hCES1 solution, and the enol ester prodrug was found to behave differently from alcohol ester prodrugs, which were metabolically activated by hCES2.
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| identifier | ISSN: 0928-0987 |
| ispartof | European journal of pharmaceutical sciences, 2019-04, Vol.132, p.125-131 |
| issn | 0928-0987 1879-0720 |
| language | eng |
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| source | Access via ScienceDirect (Elsevier) |
| subjects | Carboxylesterase Enol ester Haloperidol Prodrug Sustained release |
| title | Synthesis and evaluation of haloperidol ester prodrugs metabolically activated by human carboxylesterase |
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