Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773
Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and s...
Saved in:
Published in: | Annals of the New York Academy of Sciences 1994-11, Vol.744 (1), p.262-273 |
---|---|
Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3 |
---|---|
cites | cdi_FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3 |
container_end_page | 273 |
container_issue | 1 |
container_start_page | 262 |
container_title | Annals of the New York Academy of Sciences |
container_volume | 744 |
creator | CARTER, GEORGE W. BELL, RANDY L. MARSH, KENNAN LANNI, CARMINE AWNI, WALID M. BOUSKA, JENNIFER STEWART, ANDREW O. HANSEN, ROBERT DUBÉ, LOUISE BROOKS, DEE W. |
description | Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773. |
doi_str_mv | 10.1111/j.1749-6632.1994.tb52744.x |
format | article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_76944153</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>76944153</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3</originalsourceid><addsrcrecordid>eNqVkE1v2kAQhldVK0JIf0IlK4fe7OyXd7y5VCQKhIgSKRC1Pa3WZjZZajDxmhT-fYxA3DuXObzvPCM9hFwymrB2rhYJA6ljpQRPmNYyafKUg5TJ9hPpnqLPpEspQJxpLs7IeQgLShnPJHRIBzKeZlJ3yc20wRqrgCUWjX_H6Cc2Nq9KH5ZR5aLmFaM0Hvt1td294MoGjEarV5_7pqqjfgwZgLggX5wtA3497h55HtzNbu_j8eNwdNsfx4XggsdKAEBOncCUK3QOOOdZSi0qi5gxO6cMc1rM0zm4vJCacg1gpQQnQDiFoke-H7jrunrbYGjM0ocCy9KusNoEA0pLyVLRFq8PxaKuQqjRmXXtl7beGUbNXqBZmL0ls7dk9gLNUaDZtsffjl82-RLnp9OjsTb_ccj_-RJ3_0E2kz_9KVe8JcQHgg8Nbk8EW_81CgSk5tdkaLKnwe-H2UybofgAN0SO-A</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>76944153</pqid></control><display><type>article</type><title>Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773</title><source>Wiley Online Library All Backfiles</source><creator>CARTER, GEORGE W. ; BELL, RANDY L. ; MARSH, KENNAN ; LANNI, CARMINE ; AWNI, WALID M. ; BOUSKA, JENNIFER ; STEWART, ANDREW O. ; HANSEN, ROBERT ; DUBÉ, LOUISE ; BROOKS, DEE W.</creator><creatorcontrib>CARTER, GEORGE W. ; BELL, RANDY L. ; MARSH, KENNAN ; LANNI, CARMINE ; AWNI, WALID M. ; BOUSKA, JENNIFER ; STEWART, ANDREW O. ; HANSEN, ROBERT ; DUBÉ, LOUISE ; BROOKS, DEE W.</creatorcontrib><description>Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773.</description><identifier>ISSN: 0077-8923</identifier><identifier>EISSN: 1749-6632</identifier><identifier>DOI: 10.1111/j.1749-6632.1994.tb52744.x</identifier><identifier>PMID: 7825849</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>Animals ; Humans ; Hydroxyurea - analogs & derivatives ; Hydroxyurea - metabolism ; Leukotriene Antagonists ; Leukotrienes - biosynthesis ; Lipoxygenase Inhibitors - metabolism ; Microsomes, Liver - metabolism ; Neutrophils - metabolism ; Rats ; Stereoisomerism ; Tumor Cells, Cultured</subject><ispartof>Annals of the New York Academy of Sciences, 1994-11, Vol.744 (1), p.262-273</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3</citedby><cites>FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1749-6632.1994.tb52744.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1749-6632.1994.tb52744.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1410,27901,27902,46024,46448</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7825849$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>CARTER, GEORGE W.</creatorcontrib><creatorcontrib>BELL, RANDY L.</creatorcontrib><creatorcontrib>MARSH, KENNAN</creatorcontrib><creatorcontrib>LANNI, CARMINE</creatorcontrib><creatorcontrib>AWNI, WALID M.</creatorcontrib><creatorcontrib>BOUSKA, JENNIFER</creatorcontrib><creatorcontrib>STEWART, ANDREW O.</creatorcontrib><creatorcontrib>HANSEN, ROBERT</creatorcontrib><creatorcontrib>DUBÉ, LOUISE</creatorcontrib><creatorcontrib>BROOKS, DEE W.</creatorcontrib><title>Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773</title><title>Annals of the New York Academy of Sciences</title><addtitle>Ann N Y Acad Sci</addtitle><description>Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773.</description><subject>Animals</subject><subject>Humans</subject><subject>Hydroxyurea - analogs & derivatives</subject><subject>Hydroxyurea - metabolism</subject><subject>Leukotriene Antagonists</subject><subject>Leukotrienes - biosynthesis</subject><subject>Lipoxygenase Inhibitors - metabolism</subject><subject>Microsomes, Liver - metabolism</subject><subject>Neutrophils - metabolism</subject><subject>Rats</subject><subject>Stereoisomerism</subject><subject>Tumor Cells, Cultured</subject><issn>0077-8923</issn><issn>1749-6632</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1994</creationdate><recordtype>article</recordtype><recordid>eNqVkE1v2kAQhldVK0JIf0IlK4fe7OyXd7y5VCQKhIgSKRC1Pa3WZjZZajDxmhT-fYxA3DuXObzvPCM9hFwymrB2rhYJA6ljpQRPmNYyafKUg5TJ9hPpnqLPpEspQJxpLs7IeQgLShnPJHRIBzKeZlJ3yc20wRqrgCUWjX_H6Cc2Nq9KH5ZR5aLmFaM0Hvt1td294MoGjEarV5_7pqqjfgwZgLggX5wtA3497h55HtzNbu_j8eNwdNsfx4XggsdKAEBOncCUK3QOOOdZSi0qi5gxO6cMc1rM0zm4vJCacg1gpQQnQDiFoke-H7jrunrbYGjM0ocCy9KusNoEA0pLyVLRFq8PxaKuQqjRmXXtl7beGUbNXqBZmL0ls7dk9gLNUaDZtsffjl82-RLnp9OjsTb_ccj_-RJ3_0E2kz_9KVe8JcQHgg8Nbk8EW_81CgSk5tdkaLKnwe-H2UybofgAN0SO-A</recordid><startdate>199411</startdate><enddate>199411</enddate><creator>CARTER, GEORGE W.</creator><creator>BELL, RANDY L.</creator><creator>MARSH, KENNAN</creator><creator>LANNI, CARMINE</creator><creator>AWNI, WALID M.</creator><creator>BOUSKA, JENNIFER</creator><creator>STEWART, ANDREW O.</creator><creator>HANSEN, ROBERT</creator><creator>DUBÉ, LOUISE</creator><creator>BROOKS, DEE W.</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199411</creationdate><title>Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773</title><author>CARTER, GEORGE W. ; BELL, RANDY L. ; MARSH, KENNAN ; LANNI, CARMINE ; AWNI, WALID M. ; BOUSKA, JENNIFER ; STEWART, ANDREW O. ; HANSEN, ROBERT ; DUBÉ, LOUISE ; BROOKS, DEE W.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1994</creationdate><topic>Animals</topic><topic>Humans</topic><topic>Hydroxyurea - analogs & derivatives</topic><topic>Hydroxyurea - metabolism</topic><topic>Leukotriene Antagonists</topic><topic>Leukotrienes - biosynthesis</topic><topic>Lipoxygenase Inhibitors - metabolism</topic><topic>Microsomes, Liver - metabolism</topic><topic>Neutrophils - metabolism</topic><topic>Rats</topic><topic>Stereoisomerism</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CARTER, GEORGE W.</creatorcontrib><creatorcontrib>BELL, RANDY L.</creatorcontrib><creatorcontrib>MARSH, KENNAN</creatorcontrib><creatorcontrib>LANNI, CARMINE</creatorcontrib><creatorcontrib>AWNI, WALID M.</creatorcontrib><creatorcontrib>BOUSKA, JENNIFER</creatorcontrib><creatorcontrib>STEWART, ANDREW O.</creatorcontrib><creatorcontrib>HANSEN, ROBERT</creatorcontrib><creatorcontrib>DUBÉ, LOUISE</creatorcontrib><creatorcontrib>BROOKS, DEE W.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Annals of the New York Academy of Sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CARTER, GEORGE W.</au><au>BELL, RANDY L.</au><au>MARSH, KENNAN</au><au>LANNI, CARMINE</au><au>AWNI, WALID M.</au><au>BOUSKA, JENNIFER</au><au>STEWART, ANDREW O.</au><au>HANSEN, ROBERT</au><au>DUBÉ, LOUISE</au><au>BROOKS, DEE W.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773</atitle><jtitle>Annals of the New York Academy of Sciences</jtitle><addtitle>Ann N Y Acad Sci</addtitle><date>1994-11</date><risdate>1994</risdate><volume>744</volume><issue>1</issue><spage>262</spage><epage>273</epage><pages>262-273</pages><issn>0077-8923</issn><eissn>1749-6632</eissn><abstract>Based on the knowledge that glucuronidation was a major route of metabolism of the N-hydroxyurea class of 5-lipoxygenase inhibitors, a simple in vitro glucuronidation assay was established using liver microsomes from various species, including man. Compounds that were potent inhibitors of 5-LO and showed a reduced metabolic liability in vitro were then characterized more extensively in experimental animals. This prudent usage of in vitro glucuronidation proved to be highly efficient and was indispensable in the identification of A-78773, a potent new long-acting 5-LO inhibitor. Further studies with liver microsomes revealed that glucuronidation of A-78773 was stereoselective and that the R(+) enantiomer was considerably more resistant to conjugation than the S(-) stereoisomer. Pharmacokinetic studies in experimental animals and humans confirmed the greater metabolic stability of the R(+) enantiomer. A single 400-mg oral dose of A-78773 inhibited ex vivo leukotriene biosynthesis for more than 24 hours. Since 78% of the drug plasma AUC following A-78773 administration was accounted for by the R(+) enantiomer, it is reasonable to assume that the majority of the leukotriene inhibition caused by the racemate is attributable to the R(+) enantiomer, A-79175, particularly at the later times. The equivalent 5-lipoxygenase inhibitory potency coupled with the superior pharmacokinetic profile of the R(+) enantiomer, A79175, compared to the S(-) enantiomer, A-79176, indicate that the development of this compound may be preferable to the racemate A-78773.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>7825849</pmid><doi>10.1111/j.1749-6632.1994.tb52744.x</doi><tpages>12</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0077-8923 |
ispartof | Annals of the New York Academy of Sciences, 1994-11, Vol.744 (1), p.262-273 |
issn | 0077-8923 1749-6632 |
language | eng |
recordid | cdi_proquest_miscellaneous_76944153 |
source | Wiley Online Library All Backfiles |
subjects | Animals Humans Hydroxyurea - analogs & derivatives Hydroxyurea - metabolism Leukotriene Antagonists Leukotrienes - biosynthesis Lipoxygenase Inhibitors - metabolism Microsomes, Liver - metabolism Neutrophils - metabolism Rats Stereoisomerism Tumor Cells, Cultured |
title | Stereoselective Metabolism of the 5-Lipoxygenase Inhibitor A-78773 |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-18T09%3A59%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Stereoselective%20Metabolism%20of%20the%205-Lipoxygenase%20Inhibitor%20A-78773&rft.jtitle=Annals%20of%20the%20New%20York%20Academy%20of%20Sciences&rft.au=CARTER,%20GEORGE%20W.&rft.date=1994-11&rft.volume=744&rft.issue=1&rft.spage=262&rft.epage=273&rft.pages=262-273&rft.issn=0077-8923&rft.eissn=1749-6632&rft_id=info:doi/10.1111/j.1749-6632.1994.tb52744.x&rft_dat=%3Cproquest_cross%3E76944153%3C/proquest_cross%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c3232-63777b0f3e526eff7222850ae6aee81ad01eb0cd5d7fbc4902977a447f373f6e3%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=76944153&rft_id=info:pmid/7825849&rfr_iscdi=true |