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The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro
The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite,...
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Published in: | European journal of clinical pharmacology 2001-12, Vol.57 (10), p.729-735 |
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description | The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro.
Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes.
Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects.
No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe. |
doi_str_mv | 10.1007/s00228-001-0376-7 |
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Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes.
Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects.
No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-001-0376-7</identifier><identifier>PMID: 11829203</identifier><language>eng</language><publisher>Heidelberg: Springer</publisher><subject>Adult ; Anti-Inflammatory Agents, Non-Steroidal - metabolism ; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics ; Area Under Curve ; Aryl Hydrocarbon Hydroxylases ; Biological and medical sciences ; Bones, joints and connective tissue. Antiinflammatory agents ; Cytochrome P-450 CYP2C9 ; Cytochrome P-450 Enzyme System - genetics ; Cytochrome P-450 Enzyme System - physiology ; Diclofenac - metabolism ; Diclofenac - pharmacokinetics ; Female ; Genotype & phenotype ; Humans ; In Vitro Techniques ; Losartan - metabolism ; Losartan - pharmacokinetics ; Male ; Medical sciences ; Medicin och hälsovetenskap ; Metabolism ; Metabolites ; Microsomes, Liver - metabolism ; Middle Aged ; Pharmacology. Drug treatments ; Phenotype ; Plasma ; Polymorphism, Genetic ; Steroid 16-alpha-Hydroxylase ; Steroid Hydroxylases - genetics ; Steroid Hydroxylases - physiology</subject><ispartof>European journal of clinical pharmacology, 2001-12, Vol.57 (10), p.729-735</ispartof><rights>2002 INIST-CNRS</rights><rights>Springer-Verlag 2001</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-dcd269424e3173164703ce481258bdfc9e1a050cfce350e85b1e8d05175484253</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14105810$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11829203$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:1929392$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>YASAR, Ümit</creatorcontrib><creatorcontrib>ELIASSON, Erik</creatorcontrib><creatorcontrib>FORSLUND-BERGENGREN, Cecilia</creatorcontrib><creatorcontrib>TYBRING, Gunnel</creatorcontrib><creatorcontrib>GADD, Malin</creatorcontrib><creatorcontrib>SJÖQVIST, Folke</creatorcontrib><creatorcontrib>DAHL, Marja-Liisa</creatorcontrib><title>The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><description>The polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) catalyses the metabolism of many drugs including S-warfarin, acenocoumarol, phenytoin, tolbutamide, losartan and most of the non-steroidal anti-inflammatory drugs. Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro.
Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes.
Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects.
No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.</description><subject>Adult</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - metabolism</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Aryl Hydrocarbon Hydroxylases</subject><subject>Biological and medical sciences</subject><subject>Bones, joints and connective tissue. Antiinflammatory agents</subject><subject>Cytochrome P-450 CYP2C9</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Cytochrome P-450 Enzyme System - physiology</subject><subject>Diclofenac - metabolism</subject><subject>Diclofenac - pharmacokinetics</subject><subject>Female</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Losartan - metabolism</subject><subject>Losartan - pharmacokinetics</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Microsomes, Liver - metabolism</subject><subject>Middle Aged</subject><subject>Pharmacology. Drug treatments</subject><subject>Phenotype</subject><subject>Plasma</subject><subject>Polymorphism, Genetic</subject><subject>Steroid 16-alpha-Hydroxylase</subject><subject>Steroid Hydroxylases - genetics</subject><subject>Steroid Hydroxylases - physiology</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><recordid>eNp9kk-L1EAQxRtR3NnRD-BFAqJ4iVb1n3T3cRl0FRbcw3rw1HQ6Fc2apMd0ZmW_vR0mOiDoqYuu33sUVY-xZwhvEEC_TQCcmxIASxC6KvUDtkEpeIkg8SHbAAgsK6vhjJ2ndJs5ZUE8ZmeIhlsOYsOub75RMcWeitgWuy_XfGeLrzTG-X5PRTcWc24PNPs69l0aFqjpQh9bGn1Y-nfdXSz82BzreYpP2KPW94meru-WfX7_7mb3obz6dPlxd3FVBiVhLpvQ8MpKLkmgFlhJDSKQNMiVqZs2WEIPCkIbSCggo2ok04BCraSRXIktK4--6SftD7XbT93gp3sXfefWr--5Iqes4tl8y_Q_-f0Um5PotxAtt8LyrHx1VGbsx4HS7IYuBep7P1I8JKe55BaFyeDr_4JohBaysmqZ_sVf6G08TGNemENuKi0hbylTeKTCFFOaqP0zNYJbEuCOCXD5sm5JgNNZ83x1PtQDNSfFevIMvFwBn4Lv28mPoUsnTiIogyB-ATRatlc</recordid><startdate>20011201</startdate><enddate>20011201</enddate><creator>YASAR, Ümit</creator><creator>ELIASSON, Erik</creator><creator>FORSLUND-BERGENGREN, Cecilia</creator><creator>TYBRING, Gunnel</creator><creator>GADD, Malin</creator><creator>SJÖQVIST, Folke</creator><creator>DAHL, Marja-Liisa</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>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7TK</scope><scope>7U9</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>H94</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>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope></search><sort><creationdate>20011201</creationdate><title>The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro</title><author>YASAR, Ümit ; ELIASSON, Erik ; FORSLUND-BERGENGREN, Cecilia ; TYBRING, Gunnel ; GADD, Malin ; SJÖQVIST, Folke ; DAHL, Marja-Liisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c540t-dcd269424e3173164703ce481258bdfc9e1a050cfce350e85b1e8d05175484253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adult</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - metabolism</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Aryl Hydrocarbon Hydroxylases</topic><topic>Biological and medical sciences</topic><topic>Bones, joints and connective tissue. Antiinflammatory agents</topic><topic>Cytochrome P-450 CYP2C9</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Cytochrome P-450 Enzyme System - physiology</topic><topic>Diclofenac - metabolism</topic><topic>Diclofenac - pharmacokinetics</topic><topic>Female</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Losartan - metabolism</topic><topic>Losartan - pharmacokinetics</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Microsomes, Liver - metabolism</topic><topic>Middle Aged</topic><topic>Pharmacology. 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Diclofenac is metabolised to 4'-hydroxy (OH), the major diclofenac metabolite, 3'-OH and 3'-OH-4'-methoxy metabolites by CYP2C9. The aim of the present study was to clarify the impact of the CYP2C9 polymorphism on the metabolism of diclofenac both in vivo and in vitro.
Twenty healthy volunteers with different CYP2C9 genotypes [i.e. CYP2C9*1/ *1 (n = 6), *1/*2 (n = 3), *1,/*3 (n = 5), *2/*3 (n = 4), *21*2 (n = 1), *31*3 (n = 1)] received a single 50-mg oral dose of diclofenac. Plasma pharmacokinetics [peak plasma concentration (Cmax), half-life (t 1/2) and area under the plasma concentration-time curve (AUCtotal)] and urinary recovery of diclofenac and its metabolites were compared between the genotypes. Diclofenac 4'-hydroxylation was also analysed in vitro in 16 different samples of genotyped [i.e. CYP2C9*1/*1 (n = 7), *1/*2 (n=2), *1/*3 (n = 2), *2/*3 (n = 2), *2/*2 (n = 2), *31/*3 (n = 1)] human liver microsomes.
Within each genotype group, a high variability was observed in kinetic parameters for diclofenac and 4'-OH-diclofenac (6- and 20-fold, respectively). No significant differences were found between the different genotypes either in vivo or in human liver microsomes. No correlation was found between the plasma AUC ratio of diclofenac/4'-OH-diclofenac and that of losartan/ E-3174, previously determined in the same subjects.
No relationship was found between the CYP2C9 genotype and the 4'-hydroxylation of diclofenac either in vivo or in vitro. This, together with the lack of correlation between losartan oxidation and diclofenac hydroxylation in vivo raises the question about the usefulness of diclofenac as a CYP2C9 probe.</abstract><cop>Heidelberg</cop><cop>Berlin</cop><pub>Springer</pub><pmid>11829203</pmid><doi>10.1007/s00228-001-0376-7</doi><tpages>7</tpages></addata></record> |
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subjects | Adult Anti-Inflammatory Agents, Non-Steroidal - metabolism Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics Area Under Curve Aryl Hydrocarbon Hydroxylases Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Cytochrome P-450 CYP2C9 Cytochrome P-450 Enzyme System - genetics Cytochrome P-450 Enzyme System - physiology Diclofenac - metabolism Diclofenac - pharmacokinetics Female Genotype & phenotype Humans In Vitro Techniques Losartan - metabolism Losartan - pharmacokinetics Male Medical sciences Medicin och hälsovetenskap Metabolism Metabolites Microsomes, Liver - metabolism Middle Aged Pharmacology. Drug treatments Phenotype Plasma Polymorphism, Genetic Steroid 16-alpha-Hydroxylase Steroid Hydroxylases - genetics Steroid Hydroxylases - physiology |
title | The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro |
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