Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients
Objective Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic pol...
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| Veröffentlicht in: | European journal of clinical pharmacology 2008-09, Vol.64 (9), p.871-876 |
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| container_title | European journal of clinical pharmacology |
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| creator | Bohanec Grabar, Petra Rozman, Blaž Tomšič, Matija Šuput, Daša Logar, Dušan Dolžan, Vita |
| description | Objective
Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of
CYP1A2
,
CYP2C19,
and
CYP2C9
influence leflunomide toxicity.
Methods
A genotyping approach was used to determine
CYP1A2*1F
,
CYP2C19*2, CYP2C19*17, CYP2C9*2
, and
CYP2C9*3
alleles in 105 RA patients.
Results
Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with
CYP1A2*1F
CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of
CYP1A2*1F
A allele [
P
= 0.002, odds ratio = 9.708, 95% confidence interval = 2.276–41.403]. No significant association between the
CYP2C19
and
CYP2C9
genotypes and the leflunomide toxicity was observed.
Conclusion
Our results suggest that the
CYP1A2*1F
allele may be associated with leflunomide toxicity in RA patients. |
| doi_str_mv | 10.1007/s00228-008-0498-2 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_21038074</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1547164401</sourcerecordid><originalsourceid>FETCH-LOGICAL-c461t-c4a34e68af24ac7454424eea53d9516831ebde12cd3fca3f26dc87b74b8253713</originalsourceid><addsrcrecordid>eNqFkU-L1DAYh4Mo7jj6AbxIEPRWffOnSXpcBl2FBT3owVPIpG-dLG1TkxR2vr0ZZnBBEA9JIL8nvyQ8hLxk8I4B6PcZgHPTANQhO9PwR2TDpOANA8kekw2AYI3qNFyRZznfAbC2A_GUXDEjO6UM35BwgzOW4OkSx-MU03IIeaJxoLsfX9k1p27uaTkgLfE--FCOp2jEYVznOIW-7id0ZcK50DDTdMB1ciWGnrpUDimUkOniSqh5fk6eDG7M-OKybsn3jx--7T41t19uPu-ubxsvFSt1dkKiMm7g0nktWym5RHSt6LuWKSMY7ntk3Pdi8E4MXPXe6L2We8NboZnYkrfn3iXFXyvmYqeQPY6jmzGu2XIGwoCW_wcBpNSKV_D1X-BdXNNcP1HLpDSiq5Vbws6QTzHnhINdUphcOloG9mTLnm3ZasuebNlT8atL8bqfsH84cdFTgTcXwGXvxiG52Yf8h-OguJamrRw_c7lG809MDy_89-2_AT5irJo</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>214483910</pqid></control><display><type>article</type><title>Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Bohanec Grabar, Petra ; Rozman, Blaž ; Tomšič, Matija ; Šuput, Daša ; Logar, Dušan ; Dolžan, Vita</creator><creatorcontrib>Bohanec Grabar, Petra ; Rozman, Blaž ; Tomšič, Matija ; Šuput, Daša ; Logar, Dušan ; Dolžan, Vita</creatorcontrib><description>Objective
Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of
CYP1A2
,
CYP2C19,
and
CYP2C9
influence leflunomide toxicity.
Methods
A genotyping approach was used to determine
CYP1A2*1F
,
CYP2C19*2, CYP2C19*17, CYP2C9*2
, and
CYP2C9*3
alleles in 105 RA patients.
Results
Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with
CYP1A2*1F
CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of
CYP1A2*1F
A allele [
P
= 0.002, odds ratio = 9.708, 95% confidence interval = 2.276–41.403]. No significant association between the
CYP2C19
and
CYP2C9
genotypes and the leflunomide toxicity was observed.
Conclusion
Our results suggest that the
CYP1A2*1F
allele may be associated with leflunomide toxicity in RA patients.</description><identifier>ISSN: 0031-6970</identifier><identifier>EISSN: 1432-1041</identifier><identifier>DOI: 10.1007/s00228-008-0498-2</identifier><identifier>PMID: 18496682</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Aged ; Antirheumatic Agents - toxicity ; Arthritis, Rheumatoid - drug therapy ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Cytochrome P-450 CYP1A2 - genetics ; Diarrhea - chemically induced ; Diseases of the osteoarticular system ; Dose-Response Relationship, Drug ; Drug therapy ; Female ; Genotype & phenotype ; Humans ; Inflammatory joint diseases ; Isoxazoles - toxicity ; Male ; Medical sciences ; Middle Aged ; Nausea - chemically induced ; Pharmacogenetics ; Pharmacology ; Pharmacology. Drug treatments ; Pharmacology/Toxicology ; Pilot Projects ; Polymorphism ; Polymorphism, Genetic ; Pruritus - chemically induced ; Rheumatoid arthritis ; Toxicity ; Vomiting - chemically induced</subject><ispartof>European journal of clinical pharmacology, 2008-09, Vol.64 (9), p.871-876</ispartof><rights>Springer-Verlag 2008</rights><rights>2008 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-c4a34e68af24ac7454424eea53d9516831ebde12cd3fca3f26dc87b74b8253713</citedby><cites>FETCH-LOGICAL-c461t-c4a34e68af24ac7454424eea53d9516831ebde12cd3fca3f26dc87b74b8253713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00228-008-0498-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00228-008-0498-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20627485$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18496682$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bohanec Grabar, Petra</creatorcontrib><creatorcontrib>Rozman, Blaž</creatorcontrib><creatorcontrib>Tomšič, Matija</creatorcontrib><creatorcontrib>Šuput, Daša</creatorcontrib><creatorcontrib>Logar, Dušan</creatorcontrib><creatorcontrib>Dolžan, Vita</creatorcontrib><title>Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients</title><title>European journal of clinical pharmacology</title><addtitle>Eur J Clin Pharmacol</addtitle><addtitle>Eur J Clin Pharmacol</addtitle><description>Objective
Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of
CYP1A2
,
CYP2C19,
and
CYP2C9
influence leflunomide toxicity.
Methods
A genotyping approach was used to determine
CYP1A2*1F
,
CYP2C19*2, CYP2C19*17, CYP2C9*2
, and
CYP2C9*3
alleles in 105 RA patients.
Results
Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with
CYP1A2*1F
CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of
CYP1A2*1F
A allele [
P
= 0.002, odds ratio = 9.708, 95% confidence interval = 2.276–41.403]. No significant association between the
CYP2C19
and
CYP2C9
genotypes and the leflunomide toxicity was observed.
Conclusion
Our results suggest that the
CYP1A2*1F
allele may be associated with leflunomide toxicity in RA patients.</description><subject>Aged</subject><subject>Antirheumatic Agents - toxicity</subject><subject>Arthritis, Rheumatoid - drug therapy</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cytochrome P-450 CYP1A2 - genetics</subject><subject>Diarrhea - chemically induced</subject><subject>Diseases of the osteoarticular system</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug therapy</subject><subject>Female</subject><subject>Genotype & phenotype</subject><subject>Humans</subject><subject>Inflammatory joint diseases</subject><subject>Isoxazoles - toxicity</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Nausea - chemically induced</subject><subject>Pharmacogenetics</subject><subject>Pharmacology</subject><subject>Pharmacology. Drug treatments</subject><subject>Pharmacology/Toxicology</subject><subject>Pilot Projects</subject><subject>Polymorphism</subject><subject>Polymorphism, Genetic</subject><subject>Pruritus - chemically induced</subject><subject>Rheumatoid arthritis</subject><subject>Toxicity</subject><subject>Vomiting - chemically induced</subject><issn>0031-6970</issn><issn>1432-1041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkU-L1DAYh4Mo7jj6AbxIEPRWffOnSXpcBl2FBT3owVPIpG-dLG1TkxR2vr0ZZnBBEA9JIL8nvyQ8hLxk8I4B6PcZgHPTANQhO9PwR2TDpOANA8kekw2AYI3qNFyRZznfAbC2A_GUXDEjO6UM35BwgzOW4OkSx-MU03IIeaJxoLsfX9k1p27uaTkgLfE--FCOp2jEYVznOIW-7id0ZcK50DDTdMB1ciWGnrpUDimUkOniSqh5fk6eDG7M-OKybsn3jx--7T41t19uPu-ubxsvFSt1dkKiMm7g0nktWym5RHSt6LuWKSMY7ntk3Pdi8E4MXPXe6L2We8NboZnYkrfn3iXFXyvmYqeQPY6jmzGu2XIGwoCW_wcBpNSKV_D1X-BdXNNcP1HLpDSiq5Vbws6QTzHnhINdUphcOloG9mTLnm3ZasuebNlT8atL8bqfsH84cdFTgTcXwGXvxiG52Yf8h-OguJamrRw_c7lG809MDy_89-2_AT5irJo</recordid><startdate>20080901</startdate><enddate>20080901</enddate><creator>Bohanec Grabar, Petra</creator><creator>Rozman, Blaž</creator><creator>Tomšič, Matija</creator><creator>Šuput, Daša</creator><creator>Logar, Dušan</creator><creator>Dolžan, Vita</creator><general>Springer-Verlag</general><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>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20080901</creationdate><title>Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients</title><author>Bohanec Grabar, Petra ; Rozman, Blaž ; Tomšič, Matija ; Šuput, Daša ; Logar, Dušan ; Dolžan, Vita</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-c4a34e68af24ac7454424eea53d9516831ebde12cd3fca3f26dc87b74b8253713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Aged</topic><topic>Antirheumatic Agents - toxicity</topic><topic>Arthritis, Rheumatoid - drug therapy</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cytochrome P-450 CYP1A2 - genetics</topic><topic>Diarrhea - chemically induced</topic><topic>Diseases of the osteoarticular system</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug therapy</topic><topic>Female</topic><topic>Genotype & phenotype</topic><topic>Humans</topic><topic>Inflammatory joint diseases</topic><topic>Isoxazoles - toxicity</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Nausea - chemically induced</topic><topic>Pharmacogenetics</topic><topic>Pharmacology</topic><topic>Pharmacology. Drug treatments</topic><topic>Pharmacology/Toxicology</topic><topic>Pilot Projects</topic><topic>Polymorphism</topic><topic>Polymorphism, Genetic</topic><topic>Pruritus - chemically induced</topic><topic>Rheumatoid arthritis</topic><topic>Toxicity</topic><topic>Vomiting - chemically induced</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bohanec Grabar, Petra</creatorcontrib><creatorcontrib>Rozman, Blaž</creatorcontrib><creatorcontrib>Tomšič, Matija</creatorcontrib><creatorcontrib>Šuput, Daša</creatorcontrib><creatorcontrib>Logar, Dušan</creatorcontrib><creatorcontrib>Dolžan, Vita</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>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS 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>AIDS and Cancer Research Abstracts</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>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>European journal of clinical pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bohanec Grabar, Petra</au><au>Rozman, Blaž</au><au>Tomšič, Matija</au><au>Šuput, Daša</au><au>Logar, Dušan</au><au>Dolžan, Vita</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients</atitle><jtitle>European journal of clinical pharmacology</jtitle><stitle>Eur J Clin Pharmacol</stitle><addtitle>Eur J Clin Pharmacol</addtitle><date>2008-09-01</date><risdate>2008</risdate><volume>64</volume><issue>9</issue><spage>871</spage><epage>876</epage><pages>871-876</pages><issn>0031-6970</issn><eissn>1432-1041</eissn><abstract>Objective
Leflunomide is a disease-modifying antirheumatic drug used for treating rheumatoid arthritis (RA). In vitro studies demonstrated that cytochromes P450 (CYPs), mainly CYP1A2 and CYP2C19, might be involved in leflunomide activation. The aim of our study was to investigate whether genetic polymorphisms of
CYP1A2
,
CYP2C19,
and
CYP2C9
influence leflunomide toxicity.
Methods
A genotyping approach was used to determine
CYP1A2*1F
,
CYP2C19*2, CYP2C19*17, CYP2C9*2
, and
CYP2C9*3
alleles in 105 RA patients.
Results
Leflunomide treatment was well tolerated by 62 patients, whereas 43 patients discontinued the treatment within the first year due to toxicity. Patients with
CYP1A2*1F
CC genotype had a 9.7-fold higher risk for overall leflunomide-induced toxicity than did the carriers of
CYP1A2*1F
A allele [
P
= 0.002, odds ratio = 9.708, 95% confidence interval = 2.276–41.403]. No significant association between the
CYP2C19
and
CYP2C9
genotypes and the leflunomide toxicity was observed.
Conclusion
Our results suggest that the
CYP1A2*1F
allele may be associated with leflunomide toxicity in RA patients.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>18496682</pmid><doi>10.1007/s00228-008-0498-2</doi><tpages>6</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0031-6970 |
| ispartof | European journal of clinical pharmacology, 2008-09, Vol.64 (9), p.871-876 |
| issn | 0031-6970 1432-1041 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals |
| subjects | Aged Antirheumatic Agents - toxicity Arthritis, Rheumatoid - drug therapy Biological and medical sciences Biomedical and Life Sciences Biomedicine Cytochrome P-450 CYP1A2 - genetics Diarrhea - chemically induced Diseases of the osteoarticular system Dose-Response Relationship, Drug Drug therapy Female Genotype & phenotype Humans Inflammatory joint diseases Isoxazoles - toxicity Male Medical sciences Middle Aged Nausea - chemically induced Pharmacogenetics Pharmacology Pharmacology. Drug treatments Pharmacology/Toxicology Pilot Projects Polymorphism Polymorphism, Genetic Pruritus - chemically induced Rheumatoid arthritis Toxicity Vomiting - chemically induced |
| title | Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients |
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