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Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9
1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4′-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intesti...
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| Published in: | Xenobiotica 2016-04, Vol.46 (4), p.289-295 |
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| Main Authors: | , , , , , , , , |
| Format: | Article |
| Language: | English |
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| cited_by | cdi_FETCH-LOGICAL-c502t-801ef8eeb6fe1e0bd2be614036cad6d66a1268da38151b956b5963d7d83443713 |
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| cites | cdi_FETCH-LOGICAL-c502t-801ef8eeb6fe1e0bd2be614036cad6d66a1268da38151b956b5963d7d83443713 |
| container_end_page | 295 |
| container_issue | 4 |
| container_start_page | 289 |
| container_title | Xenobiotica |
| container_volume | 46 |
| creator | Kishi, Naoki Takasuka, Akane Kokawa, Yuki Isobe, Takashi Taguchi, Maho Shigeyama, Masato Murata, Mikio Suno, Manabu Hanioka, Nobumitsu |
| description | 1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4′-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9).
2. Although the K
m
and CL
int
values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in V
max
values (liver microsomes, humans > monkeys; intestinal microsomes, humans UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4′-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys.
4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys. |
| doi_str_mv | 10.3109/00498254.2015.1074301 |
| format | article |
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2. Although the K
m
and CL
int
values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in V
max
values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K
m
or S
50
, V
max
and CL
int
or CL
max
values for the 4′-glucuronidation of liver and intestinal microsomes between humans and monkeys.
3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4′-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys.
4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.</description><identifier>ISSN: 0049-8254</identifier><identifier>EISSN: 1366-5928</identifier><identifier>DOI: 10.3109/00498254.2015.1074301</identifier><identifier>PMID: 26247833</identifier><language>eng</language><publisher>England: Taylor & Francis</publisher><subject>Adolescent ; Adult ; Aged ; Animals ; Glucuronidation ; Glucuronides - metabolism ; Glucuronosyltransferase - metabolism ; Haplorhini ; Humans ; intestinal microsomes ; Intestines - drug effects ; Intestines - metabolism ; Kinetics ; liver microsomes ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; Middle Aged ; monkeys ; raloxifene ; Raloxifene Hydrochloride - chemistry ; Raloxifene Hydrochloride - metabolism ; Raloxifene Hydrochloride - pharmacology ; Recombinant Proteins - metabolism ; Young Adult</subject><ispartof>Xenobiotica, 2016-04, Vol.46 (4), p.289-295</ispartof><rights>2015 Taylor & Francis. 2015</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-801ef8eeb6fe1e0bd2be614036cad6d66a1268da38151b956b5963d7d83443713</citedby><cites>FETCH-LOGICAL-c502t-801ef8eeb6fe1e0bd2be614036cad6d66a1268da38151b956b5963d7d83443713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26247833$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kishi, Naoki</creatorcontrib><creatorcontrib>Takasuka, Akane</creatorcontrib><creatorcontrib>Kokawa, Yuki</creatorcontrib><creatorcontrib>Isobe, Takashi</creatorcontrib><creatorcontrib>Taguchi, Maho</creatorcontrib><creatorcontrib>Shigeyama, Masato</creatorcontrib><creatorcontrib>Murata, Mikio</creatorcontrib><creatorcontrib>Suno, Manabu</creatorcontrib><creatorcontrib>Hanioka, Nobumitsu</creatorcontrib><title>Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9</title><title>Xenobiotica</title><addtitle>Xenobiotica</addtitle><description>1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4′-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9).
2. Although the K
m
and CL
int
values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in V
max
values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K
m
or S
50
, V
max
and CL
int
or CL
max
values for the 4′-glucuronidation of liver and intestinal microsomes between humans and monkeys.
3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4′-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys.
4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Glucuronidation</subject><subject>Glucuronides - metabolism</subject><subject>Glucuronosyltransferase - metabolism</subject><subject>Haplorhini</subject><subject>Humans</subject><subject>intestinal microsomes</subject><subject>Intestines - drug effects</subject><subject>Intestines - metabolism</subject><subject>Kinetics</subject><subject>liver microsomes</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>Middle Aged</subject><subject>monkeys</subject><subject>raloxifene</subject><subject>Raloxifene Hydrochloride - chemistry</subject><subject>Raloxifene Hydrochloride - metabolism</subject><subject>Raloxifene Hydrochloride - pharmacology</subject><subject>Recombinant Proteins - metabolism</subject><subject>Young Adult</subject><issn>0049-8254</issn><issn>1366-5928</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><recordid>eNp9kNFKwzAUhoMobk4fQekD2JmTtGnqlWPoFAaCbNclbVKNtslIWnU3Prttt3np1cmB7_9P-BC6BDylgNMbjKOUkziaEgzxFHASUQxHaAyUsTBOCT9G454Je2iEzrx_xxgzIOQUjQgjUcIpHaOfF1HZb10qo4LXqi1aZ42WotHWBNoElf5ULhBGdkujfKONqIJaF856Wysf2DJ4a2th_MDU1nyorb8NCmsap_N2qOmY9WIFM7jeTT6wwzM9RyelqLy62M8JWj_cr-aP4fJ58TSfLcMixqQJOQZVcqVyVipQOJckVwwiTFkhJJOMCSCMS0E5xJCnMcvjlFGZSE6jiCZAJyje9fY_906V2cbpWrhtBjjrfWYHn1nvM9v77HJXu9ymzWsl_1IHgR1wtwO0Ka2rxZd1lcwasa2sK50whfZ9_383fgE3VYR7</recordid><startdate>20160402</startdate><enddate>20160402</enddate><creator>Kishi, Naoki</creator><creator>Takasuka, Akane</creator><creator>Kokawa, Yuki</creator><creator>Isobe, Takashi</creator><creator>Taguchi, Maho</creator><creator>Shigeyama, Masato</creator><creator>Murata, Mikio</creator><creator>Suno, Manabu</creator><creator>Hanioka, Nobumitsu</creator><general>Taylor & Francis</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20160402</creationdate><title>Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9</title><author>Kishi, Naoki ; Takasuka, Akane ; Kokawa, Yuki ; Isobe, Takashi ; Taguchi, Maho ; Shigeyama, Masato ; Murata, Mikio ; Suno, Manabu ; Hanioka, Nobumitsu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-801ef8eeb6fe1e0bd2be614036cad6d66a1268da38151b956b5963d7d83443713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Glucuronidation</topic><topic>Glucuronides - metabolism</topic><topic>Glucuronosyltransferase - metabolism</topic><topic>Haplorhini</topic><topic>Humans</topic><topic>intestinal microsomes</topic><topic>Intestines - drug effects</topic><topic>Intestines - metabolism</topic><topic>Kinetics</topic><topic>liver microsomes</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>Middle Aged</topic><topic>monkeys</topic><topic>raloxifene</topic><topic>Raloxifene Hydrochloride - chemistry</topic><topic>Raloxifene Hydrochloride - metabolism</topic><topic>Raloxifene Hydrochloride - pharmacology</topic><topic>Recombinant Proteins - metabolism</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kishi, Naoki</creatorcontrib><creatorcontrib>Takasuka, Akane</creatorcontrib><creatorcontrib>Kokawa, Yuki</creatorcontrib><creatorcontrib>Isobe, Takashi</creatorcontrib><creatorcontrib>Taguchi, Maho</creatorcontrib><creatorcontrib>Shigeyama, Masato</creatorcontrib><creatorcontrib>Murata, Mikio</creatorcontrib><creatorcontrib>Suno, Manabu</creatorcontrib><creatorcontrib>Hanioka, Nobumitsu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Xenobiotica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kishi, Naoki</au><au>Takasuka, Akane</au><au>Kokawa, Yuki</au><au>Isobe, Takashi</au><au>Taguchi, Maho</au><au>Shigeyama, Masato</au><au>Murata, Mikio</au><au>Suno, Manabu</au><au>Hanioka, Nobumitsu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9</atitle><jtitle>Xenobiotica</jtitle><addtitle>Xenobiotica</addtitle><date>2016-04-02</date><risdate>2016</risdate><volume>46</volume><issue>4</issue><spage>289</spage><epage>295</epage><pages>289-295</pages><issn>0049-8254</issn><eissn>1366-5928</eissn><abstract>1. Raloxifene is an antiestrogen that has been marketed for the treatment of osteoporosis, and is metabolized into 6- and 4′-glucuronides by UDP-glucuronosyltransferase (UGT) enzymes. In this study, the in vitro glucuronidation of raloxifene in humans and monkeys was examined using liver and intestinal microsomes and recombinant UGT enzymes (UGT1A1, UGT1A8 and UGT1A9).
2. Although the K
m
and CL
int
values for the 6-glucuronidation of liver and intestinal microsomes were similar between humans and monkeys, and species differences in V
max
values (liver microsomes, humans > monkeys; intestinal microsomes, humans < monkeys) were observed, no significant differences were noted in the K
m
or S
50
, V
max
and CL
int
or CL
max
values for the 4′-glucuronidation of liver and intestinal microsomes between humans and monkeys.
3. The activities of 6-glucuronidation in recombinant UGT enzymes were UGT1A1 > UGT1A8 >UGT1A9 for humans, and UGT1A8 > UGT1A1 > UGT1A9 for monkeys. The activities of 4′-glucuronidation were UGT1A8 > UGT1A1 > UGT1A9 in humans and monkeys.
4. These results demonstrated that the profiles for the hepatic and intestinal glucuronidation of raloxifene by microsomes were moderately different between humans and monkeys.</abstract><cop>England</cop><pub>Taylor & Francis</pub><pmid>26247833</pmid><doi>10.3109/00498254.2015.1074301</doi><tpages>7</tpages></addata></record> |
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| identifier | ISSN: 0049-8254 |
| ispartof | Xenobiotica, 2016-04, Vol.46 (4), p.289-295 |
| issn | 0049-8254 1366-5928 |
| language | eng |
| recordid | cdi_pubmed_primary_26247833 |
| source | Taylor and Francis:Jisc Collections:Taylor and Francis Read and Publish Agreement 2024-2025:Medical Collection (Reading list) |
| subjects | Adolescent Adult Aged Animals Glucuronidation Glucuronides - metabolism Glucuronosyltransferase - metabolism Haplorhini Humans intestinal microsomes Intestines - drug effects Intestines - metabolism Kinetics liver microsomes Microsomes, Liver - drug effects Microsomes, Liver - metabolism Middle Aged monkeys raloxifene Raloxifene Hydrochloride - chemistry Raloxifene Hydrochloride - metabolism Raloxifene Hydrochloride - pharmacology Recombinant Proteins - metabolism Young Adult |
| title | Raloxifene glucuronidation in liver and intestinal microsomes of humans and monkeys: contribution of UGT1A1, UGT1A8 and UGT1A9 |
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