Species Difference in Nisoldipine Oxidation Activity in the Small Intestine
Species difference in nisoldipine oxidation activities was investigated using small intestinal microsomes of rats, guinea pigs, dogs, monkeys and humans. The oxidation activities were estimated by measuring metabolites formation (BAY o 3199 and BAY r 9425) of nisoldipine. For the preparation of smal...
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Veröffentlicht in: | DRUG METABOLISM AND PHARMACOKINETICS 2002, Vol.17 (5), p.427-436 |
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description | Species difference in nisoldipine oxidation activities was investigated using small intestinal microsomes of rats, guinea pigs, dogs, monkeys and humans. The oxidation activities were estimated by measuring metabolites formation (BAY o 3199 and BAY r 9425) of nisoldipine. For the preparation of small intestinal microsomes of various animal species, the effect of protease inhibitors was preliminarily investigated. The formation of BAY o 3199 significantly increased in the rat small intestinal microsomes prepared with trypsin inhibitor. Using the trypsin inhibitor-treated small intestinal microsomes of various animals, metabolic intrinsic clearances (CLint, in vitro) for BAY o 3199 and BAY r 9425 formations were estimated based on an Eadie-Hofstee plot. The total CLint, in vitro estimated by the sum of CLint, in vitro for both formations in the small intestines of all species was much lower than that in the liver. There was a marked species difference in the nisoldipine oxidation activities in the small intestines, with the rank order being humans = monkeys > dogs > rats > guinea pigs, versus the following order in the liver: rats > monkeys = guinea pigs > humans > dogs. The formations of both BAY o 3199 and BAY r 9425 in the human intestinal microsomes were inhibited by pretreatment with troleandomycin (TAO) and antiserum against CYP3A4. Similar inhibition profile by TAO was obtained from the monkey intestinal microsomes. These results implied that monkeys would be a good predictor of human small intestinal metabolism for CYP3A4 substrates. |
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Research Center Kyoto. Bayer Yakuhin ; Graduate School of Pharmaceutical Sciences. University of Tokyo</creatorcontrib><description>Species difference in nisoldipine oxidation activities was investigated using small intestinal microsomes of rats, guinea pigs, dogs, monkeys and humans. The oxidation activities were estimated by measuring metabolites formation (BAY o 3199 and BAY r 9425) of nisoldipine. For the preparation of small intestinal microsomes of various animal species, the effect of protease inhibitors was preliminarily investigated. The formation of BAY o 3199 significantly increased in the rat small intestinal microsomes prepared with trypsin inhibitor. Using the trypsin inhibitor-treated small intestinal microsomes of various animals, metabolic intrinsic clearances (CLint, in vitro) for BAY o 3199 and BAY r 9425 formations were estimated based on an Eadie-Hofstee plot. The total CLint, in vitro estimated by the sum of CLint, in vitro for both formations in the small intestines of all species was much lower than that in the liver. There was a marked species difference in the nisoldipine oxidation activities in the small intestines, with the rank order being humans = monkeys > dogs > rats > guinea pigs, versus the following order in the liver: rats > monkeys = guinea pigs > humans > dogs. The formations of both BAY o 3199 and BAY r 9425 in the human intestinal microsomes were inhibited by pretreatment with troleandomycin (TAO) and antiserum against CYP3A4. Similar inhibition profile by TAO was obtained from the monkey intestinal microsomes. These results implied that monkeys would be a good predictor of human small intestinal metabolism for CYP3A4 substrates.</description><identifier>ISSN: 1347-4367</identifier><identifier>EISSN: 1880-0920</identifier><identifier>DOI: 10.2133/dmpk.17.427</identifier><identifier>PMID: 15618694</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>CYP3A ; human ; intestinal metabolism ; monkey ; nisoldipine ; species difference</subject><ispartof>DRUG METABOLISM AND PHARMACOKINETICS, 2002, Vol.17 (5), p.427-436</ispartof><rights>2002 The Japanese Society for the Study of Xenobiotics</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c502t-d4a2c5862a0e08d9b7705aeca245f7ce71c749c1355e5a926cc450f64dbffc6c3</citedby><cites>FETCH-LOGICAL-c502t-d4a2c5862a0e08d9b7705aeca245f7ce71c749c1355e5a926cc450f64dbffc6c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,4024,27923,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15618694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Komura, Hiroshi</creatorcontrib><creatorcontrib>Yasuda, Motoko</creatorcontrib><creatorcontrib>Yoshida, Nagahiro H.</creatorcontrib><creatorcontrib>Sugiyama, Yuichi</creatorcontrib><creatorcontrib>Department of Pharmacokinetics. Research Center Kyoto. Bayer Yakuhin</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences. University of Tokyo</creatorcontrib><title>Species Difference in Nisoldipine Oxidation Activity in the Small Intestine</title><title>DRUG METABOLISM AND PHARMACOKINETICS</title><addtitle>Drug Metab Pharmacokinet</addtitle><description>Species difference in nisoldipine oxidation activities was investigated using small intestinal microsomes of rats, guinea pigs, dogs, monkeys and humans. The oxidation activities were estimated by measuring metabolites formation (BAY o 3199 and BAY r 9425) of nisoldipine. For the preparation of small intestinal microsomes of various animal species, the effect of protease inhibitors was preliminarily investigated. The formation of BAY o 3199 significantly increased in the rat small intestinal microsomes prepared with trypsin inhibitor. Using the trypsin inhibitor-treated small intestinal microsomes of various animals, metabolic intrinsic clearances (CLint, in vitro) for BAY o 3199 and BAY r 9425 formations were estimated based on an Eadie-Hofstee plot. The total CLint, in vitro estimated by the sum of CLint, in vitro for both formations in the small intestines of all species was much lower than that in the liver. There was a marked species difference in the nisoldipine oxidation activities in the small intestines, with the rank order being humans = monkeys > dogs > rats > guinea pigs, versus the following order in the liver: rats > monkeys = guinea pigs > humans > dogs. The formations of both BAY o 3199 and BAY r 9425 in the human intestinal microsomes were inhibited by pretreatment with troleandomycin (TAO) and antiserum against CYP3A4. Similar inhibition profile by TAO was obtained from the monkey intestinal microsomes. These results implied that monkeys would be a good predictor of human small intestinal metabolism for CYP3A4 substrates.</description><subject>CYP3A</subject><subject>human</subject><subject>intestinal metabolism</subject><subject>monkey</subject><subject>nisoldipine</subject><subject>species difference</subject><issn>1347-4367</issn><issn>1880-0920</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><recordid>eNptkU1v1DAQhiMEoh9w4o5y4oKy-NvJsWoprajooXC2vOOJcEniYHsr-u-Z1a7EhYM9lvzoGc_rpnnH2UZwKT-Fef214XajhH3RnPK-Zx0bBHtJZ6lsp6SxJ81ZKY-MSamVeN2ccG14bwZ12nx9WBEilvYqjiNmXADbuLTfYklTiGtcsL3_E4OvMS3tBdT4FOvznqg_sX2Y_TS1t0vFUol807wa_VTw7bGeNz-uP3-_vOnu7r_cXl7cdaCZqF1QXoDujfAMWR-GrbVMewQvlB4toOVg1QBcao3aD8IAKM1Go8J2HMGAPG8-HLxrTr931NvNsQBOk18w7YqzYlCcFAR-PICQUykZR7fmOPv87Dhz--zcPjvHraPsiH5_1O62M4Z_7DEsAq4PAN1G8FNaJpraPaZdXmheB4nPWP3WCcaEY4zTXFRokZ42aQy3xuxF-iBCSukpYnaF_oCiDzEjVBdS_O8L_wL455NS</recordid><startdate>2002</startdate><enddate>2002</enddate><creator>Komura, Hiroshi</creator><creator>Yasuda, Motoko</creator><creator>Yoshida, Nagahiro H.</creator><creator>Sugiyama, Yuichi</creator><general>Elsevier Ltd</general><general>Japanese Society for the Study of Xenobiotics</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>2002</creationdate><title>Species Difference in Nisoldipine Oxidation Activity in the Small Intestine</title><author>Komura, Hiroshi ; Yasuda, Motoko ; Yoshida, Nagahiro H. ; Sugiyama, Yuichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c502t-d4a2c5862a0e08d9b7705aeca245f7ce71c749c1355e5a926cc450f64dbffc6c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>CYP3A</topic><topic>human</topic><topic>intestinal metabolism</topic><topic>monkey</topic><topic>nisoldipine</topic><topic>species difference</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Komura, Hiroshi</creatorcontrib><creatorcontrib>Yasuda, Motoko</creatorcontrib><creatorcontrib>Yoshida, Nagahiro H.</creatorcontrib><creatorcontrib>Sugiyama, Yuichi</creatorcontrib><creatorcontrib>Department of Pharmacokinetics. Research Center Kyoto. Bayer Yakuhin</creatorcontrib><creatorcontrib>Graduate School of Pharmaceutical Sciences. University of Tokyo</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Komura, Hiroshi</au><au>Yasuda, Motoko</au><au>Yoshida, Nagahiro H.</au><au>Sugiyama, Yuichi</au><aucorp>Department of Pharmacokinetics. Research Center Kyoto. Bayer Yakuhin</aucorp><aucorp>Graduate School of Pharmaceutical Sciences. University of Tokyo</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Species Difference in Nisoldipine Oxidation Activity in the Small Intestine</atitle><jtitle>DRUG METABOLISM AND PHARMACOKINETICS</jtitle><addtitle>Drug Metab Pharmacokinet</addtitle><date>2002</date><risdate>2002</risdate><volume>17</volume><issue>5</issue><spage>427</spage><epage>436</epage><pages>427-436</pages><issn>1347-4367</issn><eissn>1880-0920</eissn><abstract>Species difference in nisoldipine oxidation activities was investigated using small intestinal microsomes of rats, guinea pigs, dogs, monkeys and humans. The oxidation activities were estimated by measuring metabolites formation (BAY o 3199 and BAY r 9425) of nisoldipine. For the preparation of small intestinal microsomes of various animal species, the effect of protease inhibitors was preliminarily investigated. The formation of BAY o 3199 significantly increased in the rat small intestinal microsomes prepared with trypsin inhibitor. Using the trypsin inhibitor-treated small intestinal microsomes of various animals, metabolic intrinsic clearances (CLint, in vitro) for BAY o 3199 and BAY r 9425 formations were estimated based on an Eadie-Hofstee plot. The total CLint, in vitro estimated by the sum of CLint, in vitro for both formations in the small intestines of all species was much lower than that in the liver. There was a marked species difference in the nisoldipine oxidation activities in the small intestines, with the rank order being humans = monkeys > dogs > rats > guinea pigs, versus the following order in the liver: rats > monkeys = guinea pigs > humans > dogs. The formations of both BAY o 3199 and BAY r 9425 in the human intestinal microsomes were inhibited by pretreatment with troleandomycin (TAO) and antiserum against CYP3A4. Similar inhibition profile by TAO was obtained from the monkey intestinal microsomes. These results implied that monkeys would be a good predictor of human small intestinal metabolism for CYP3A4 substrates.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>15618694</pmid><doi>10.2133/dmpk.17.427</doi><tpages>10</tpages></addata></record> |
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subjects | CYP3A human intestinal metabolism monkey nisoldipine species difference |
title | Species Difference in Nisoldipine Oxidation Activity in the Small Intestine |
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