Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats
To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats. The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin)...
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| Veröffentlicht in: | Pharmaceutical research 2003-05, Vol.20 (5), p.745-748 |
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| creator | AIBA, Tetsuya TAKEHARA, Yutaka OKUNO, Marie HASHIMOTO, Yukiya |
| description | To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats.
The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis.
Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver.
Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine. |
| doi_str_mv | 10.1023/a:1023429401738 |
| format | Article |
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The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis.
Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver.
Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.</description><identifier>ISSN: 0724-8741</identifier><identifier>EISSN: 1573-904X</identifier><identifier>DOI: 10.1023/a:1023429401738</identifier><identifier>PMID: 12751629</identifier><identifier>CODEN: PHREEB</identifier><language>eng</language><publisher>New York, NY: Springer</publisher><subject>Animals ; Biological and medical sciences ; Cytochrome P-450 CYP3A ; Cytochrome P-450 Enzyme System - metabolism ; General pharmacology ; In Vitro Techniques ; Intestines - enzymology ; Male ; Medical sciences ; Microsomes, Liver - enzymology ; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions ; Pharmacology. Drug treatments ; Rats ; Rats, Wistar ; Substrate Specificity</subject><ispartof>Pharmaceutical research, 2003-05, Vol.20 (5), p.745-748</ispartof><rights>2003 INIST-CNRS</rights><rights>Copyright Kluwer Academic Publishers May 2003</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c401t-43ad2c89aa39d44f4caa3345344de7a89075b401bf7a1f31cb2def39a21903ff3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27922,27923</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14771844$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12751629$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>AIBA, Tetsuya</creatorcontrib><creatorcontrib>TAKEHARA, Yutaka</creatorcontrib><creatorcontrib>OKUNO, Marie</creatorcontrib><creatorcontrib>HASHIMOTO, Yukiya</creatorcontrib><title>Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats</title><title>Pharmaceutical research</title><addtitle>Pharm Res</addtitle><description>To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats.
The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis.
Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver.
Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cytochrome P-450 CYP3A</subject><subject>Cytochrome P-450 Enzyme System - metabolism</subject><subject>General pharmacology</subject><subject>In Vitro Techniques</subject><subject>Intestines - enzymology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Microsomes, Liver - enzymology</subject><subject>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</subject><subject>Pharmacology. Drug treatments</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Substrate Specificity</subject><issn>0724-8741</issn><issn>1573-904X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNpdkM1LxDAQxYMouq6evUkQ9FbNx3TTeFsWv2DBPSgoCGWaJlhpmzVpEf97I64Int5j3o_hzRByxNk5Z0Je4OW3gNDAuJLFFpnwXMlMM3jaJhOmBGSFAr5H9mN8Y4wVXMMu2eNC5Xwm9IS8rLwP1PgQbItD43ta2eHD2p42_WDj0PTYUuxr-mrXKTe0swNWvk0uYAKod3TxvJJzoHGs4vAzbPrvNB6QHYdttIcbnZLH66uHxW22vL-5W8yXmUm1hwwk1sIUGlHqGsCBSU5CLgFqq7DQTOVVIiunkDvJTSVq66RGwTWTzskpOfvZuw7-fUyty66JxrYt9taPsVRSzADSg6bk5B_45seQToylEGKmuM55go430Fh1ti7XoekwfJa_T0vA6QbAaLB1AXvTxD8OlOIFgPwC2at66A</recordid><startdate>20030501</startdate><enddate>20030501</enddate><creator>AIBA, Tetsuya</creator><creator>TAKEHARA, Yutaka</creator><creator>OKUNO, Marie</creator><creator>HASHIMOTO, Yukiya</creator><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope></search><sort><creationdate>20030501</creationdate><title>Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats</title><author>AIBA, Tetsuya ; TAKEHARA, Yutaka ; OKUNO, Marie ; HASHIMOTO, Yukiya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c401t-43ad2c89aa39d44f4caa3345344de7a89075b401bf7a1f31cb2def39a21903ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cytochrome P-450 CYP3A</topic><topic>Cytochrome P-450 Enzyme System - metabolism</topic><topic>General pharmacology</topic><topic>In Vitro Techniques</topic><topic>Intestines - enzymology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Microsomes, Liver - enzymology</topic><topic>Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions</topic><topic>Pharmacology. Drug treatments</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>AIBA, Tetsuya</creatorcontrib><creatorcontrib>TAKEHARA, Yutaka</creatorcontrib><creatorcontrib>OKUNO, Marie</creatorcontrib><creatorcontrib>HASHIMOTO, Yukiya</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><jtitle>Pharmaceutical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>AIBA, Tetsuya</au><au>TAKEHARA, Yutaka</au><au>OKUNO, Marie</au><au>HASHIMOTO, Yukiya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats</atitle><jtitle>Pharmaceutical research</jtitle><addtitle>Pharm Res</addtitle><date>2003-05-01</date><risdate>2003</risdate><volume>20</volume><issue>5</issue><spage>745</spage><epage>748</epage><pages>745-748</pages><issn>0724-8741</issn><eissn>1573-904X</eissn><coden>PHREEB</coden><abstract>To clarify the contribution of the intestinal first-pass metabolism to the drug bioavailability, the correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates was investigated in rats.
The metabolic rates of four compounds (lidocaine, quinidine, nifedidpine, and rifabutin) were examined with excised intestinal tissues and liver microsomes. The intestinal and hepatic expression of CYP3A1/23 and CYP3A2 was evaluated by Western blot analysis.
Rifabutin was metabolized fastest, and lidocaine was metabolized slowest in excised intestinal tissues. By contrast, lidocaine was metabolized fastest and rifabutin was the slowest in liver microsomes. The hepatic metabolism of lidocaine was inhibited by a CYP2D6 substrate desipramine, not by a CYP3A4 inhibitor ketoconazole. In addition, members of the CYP3A subfamily expressed in the intestine were different from those expressed in the liver.
Poor correlation between the intestinal and hepatic metabolism of human CYP3A4 substrates in rats may be caused by the contribution of the CYP2D subfamily to the drug metabolisms in the liver and also by the unique expression of the CYP3A subfamily in the intestine.</abstract><cop>New York, NY</cop><pub>Springer</pub><pmid>12751629</pmid><doi>10.1023/a:1023429401738</doi><tpages>4</tpages></addata></record> |
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| subjects | Animals Biological and medical sciences Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System - metabolism General pharmacology In Vitro Techniques Intestines - enzymology Male Medical sciences Microsomes, Liver - enzymology Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions Pharmacology. Drug treatments Rats Rats, Wistar Substrate Specificity |
| title | Poor correlation between intestinal and hepatic metabolic rates of CYP3A4 substrates in rats |
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