Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation
Summary We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentratio...
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| Veröffentlicht in: | Transplant international 2012-04, Vol.25 (4), p.471-480 |
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| creator | Gervasini, Guillermo Garcia, Montserrat Macias, Rosa María Cubero, Juan Jose Caravaca, Francisco Benitez, Julio |
| description | Summary
We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus. |
| doi_str_mv | 10.1111/j.1432-2277.2012.01446.x |
| format | Article |
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We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.</description><identifier>ISSN: 0934-0874</identifier><identifier>EISSN: 1432-2277</identifier><identifier>DOI: 10.1111/j.1432-2277.2012.01446.x</identifier><identifier>PMID: 22369694</identifier><language>eng</language><publisher>Oxford, UK: Blackwell Publishing Ltd</publisher><subject>ABCB1 ; Adult ; ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics ; CYP3A ; Cytochrome P-450 CYP3A - genetics ; Cytochrome P-450 Enzyme System - genetics ; Graft Rejection - genetics ; Humans ; Kidney Transplantation ; Polymorphism, Genetic ; polymorphisms ; renal transplant ; Retrospective Studies ; tacrolimus ; Tacrolimus - administration & dosage ; Tacrolimus - pharmacokinetics ; Tacrolimus - pharmacology ; Treatment Outcome</subject><ispartof>Transplant international, 2012-04, Vol.25 (4), p.471-480</ispartof><rights>2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation</rights><rights>2012 The Authors. Transplant International © 2012 European Society for Organ Transplantation.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4516-ae1bed9ce2391a2ccc69375492d90ea5bfe201c9651a601c6c83429f450470493</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fj.1432-2277.2012.01446.x$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fj.1432-2277.2012.01446.x$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>315,781,785,1418,27929,27930,45579,45580</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22369694$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gervasini, Guillermo</creatorcontrib><creatorcontrib>Garcia, Montserrat</creatorcontrib><creatorcontrib>Macias, Rosa María</creatorcontrib><creatorcontrib>Cubero, Juan Jose</creatorcontrib><creatorcontrib>Caravaca, Francisco</creatorcontrib><creatorcontrib>Benitez, Julio</creatorcontrib><title>Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation</title><title>Transplant international</title><addtitle>Transpl Int</addtitle><description>Summary
We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.</description><subject>ABCB1</subject><subject>Adult</subject><subject>ATP Binding Cassette Transporter, Subfamily B</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</subject><subject>CYP3A</subject><subject>Cytochrome P-450 CYP3A - genetics</subject><subject>Cytochrome P-450 Enzyme System - genetics</subject><subject>Graft Rejection - genetics</subject><subject>Humans</subject><subject>Kidney Transplantation</subject><subject>Polymorphism, Genetic</subject><subject>polymorphisms</subject><subject>renal transplant</subject><subject>Retrospective Studies</subject><subject>tacrolimus</subject><subject>Tacrolimus - administration & dosage</subject><subject>Tacrolimus - pharmacokinetics</subject><subject>Tacrolimus - pharmacology</subject><subject>Treatment Outcome</subject><issn>0934-0874</issn><issn>1432-2277</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kV1PwjAUhhujUUT_gmni9Wa_1tELLwxRJCFq_L5rSilS2NbZdhH-vRsovelJz_Oe9LwvABCjFLfnapliRklCSJ6nBGGSIswYT9cHoLdvHIIeEpQlaJCzE3AawhIhRAYZOgYnhFAuuGA9UI_LWukI3Rx-mcpEq2Htik3pfL2woQzQVTAq7V1hyybAeqF8qbRb2S0boKpmMC4M1IWtrFYFdE3UrjTdQG-q9iF6VYW6UFVU0brqDBzNVRHM-d_dB293t6_D-2TyOBoPbyaJZhnmiTJ4amZCG0IFVkRrzQXNMybITCCjsunctItrwTOseFtwPaCMiDnLEMsRE7QPLndza---GxOiXLrGtx8KEuecD4QQuKMu_qhmWpqZrL0tld_If4Na4HoH_NjCbPZ9jGQXhFzKzm_Z-S27IOQ2CLmWr8_jrmr1yU5vQzTrvV75leR5u5D8eBjJl3f0_vRJJ5LQXyBQjHY</recordid><startdate>201204</startdate><enddate>201204</enddate><creator>Gervasini, Guillermo</creator><creator>Garcia, Montserrat</creator><creator>Macias, Rosa María</creator><creator>Cubero, Juan Jose</creator><creator>Caravaca, Francisco</creator><creator>Benitez, Julio</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QO</scope><scope>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope></search><sort><creationdate>201204</creationdate><title>Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation</title><author>Gervasini, Guillermo ; Garcia, Montserrat ; Macias, Rosa María ; Cubero, Juan Jose ; Caravaca, Francisco ; Benitez, Julio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4516-ae1bed9ce2391a2ccc69375492d90ea5bfe201c9651a601c6c83429f450470493</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>ABCB1</topic><topic>Adult</topic><topic>ATP Binding Cassette Transporter, Subfamily B</topic><topic>ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics</topic><topic>CYP3A</topic><topic>Cytochrome P-450 CYP3A - genetics</topic><topic>Cytochrome P-450 Enzyme System - genetics</topic><topic>Graft Rejection - genetics</topic><topic>Humans</topic><topic>Kidney Transplantation</topic><topic>Polymorphism, Genetic</topic><topic>polymorphisms</topic><topic>renal transplant</topic><topic>Retrospective Studies</topic><topic>tacrolimus</topic><topic>Tacrolimus - administration & dosage</topic><topic>Tacrolimus - pharmacokinetics</topic><topic>Tacrolimus - pharmacology</topic><topic>Treatment Outcome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gervasini, Guillermo</creatorcontrib><creatorcontrib>Garcia, Montserrat</creatorcontrib><creatorcontrib>Macias, Rosa María</creatorcontrib><creatorcontrib>Cubero, Juan Jose</creatorcontrib><creatorcontrib>Caravaca, Francisco</creatorcontrib><creatorcontrib>Benitez, Julio</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Transplant international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gervasini, Guillermo</au><au>Garcia, Montserrat</au><au>Macias, Rosa María</au><au>Cubero, Juan Jose</au><au>Caravaca, Francisco</au><au>Benitez, Julio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation</atitle><jtitle>Transplant international</jtitle><addtitle>Transpl Int</addtitle><date>2012-04</date><risdate>2012</risdate><volume>25</volume><issue>4</issue><spage>471</spage><epage>480</epage><pages>471-480</pages><issn>0934-0874</issn><eissn>1432-2277</eissn><abstract>Summary
We retrospectively examined the association of polymorphisms in the CYP3A, CYP2J2, CYP2C8, and ABCB1 genes with pharmacokinetic (PKs) and pharmacodynamic (PDs) parameters of tacrolimus in 103 renal transplant recipients for a period of 1 year. CYP3A5 expressers had lower predose concentrations (C0)/dose and higher dose requirements than nonexpressers throughout the study. Among CYP3A5*1 carriers, those also carrying the CYP3A4*1B allele showed the lowest C0/dose, as compared with CYP3A4*1/CYP3A5*3 carriers (54.28 ± 26.45, 59.12 ± 24.00, 62.43 ± 41.12, and 57.01 ± 17.34 vs. 112.37 ± 76.60, 123.21 ± 59.57, 163.34 ± 76.23, and 183.07 ± 107.82 at 1 week, 1 month, 5 months, and 1 year after transplantation). In addition, CYP3A4*1B/CYP3A5*1 carriers showed significantly lower dose‐corrected exposure than CYP3A4*1/CYP3A5*1 carriers 1 year after transplantation (57.01 ± 17.34 vs. 100.09 ± 24.78; P = 0.016). Only the ABCB1 TGC (3435‐2677‐1236) haplotype showed a consistent association with PDs (nephrotoxicity; OR = 4.73; CI: 1.3–16.7; P = 0.02). Our findings indicate that the CYP3A4*1B‐CYP3A5*1 haplotype may have a more profound impact in tacrolimus PKs than the CYP3A5*1 allele. This study does not support a critical role of the CYP450 or ABCB1 single nucleotide polymorphisms in the occurrence of toxicity or acute rejection in renal transplant recipients treated with tacrolimus.</abstract><cop>Oxford, UK</cop><pub>Blackwell Publishing Ltd</pub><pmid>22369694</pmid><doi>10.1111/j.1432-2277.2012.01446.x</doi><tpages>10</tpages></addata></record> |
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| ispartof | Transplant international, 2012-04, Vol.25 (4), p.471-480 |
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| subjects | ABCB1 Adult ATP Binding Cassette Transporter, Subfamily B ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics CYP3A Cytochrome P-450 CYP3A - genetics Cytochrome P-450 Enzyme System - genetics Graft Rejection - genetics Humans Kidney Transplantation Polymorphism, Genetic polymorphisms renal transplant Retrospective Studies tacrolimus Tacrolimus - administration & dosage Tacrolimus - pharmacokinetics Tacrolimus - pharmacology Treatment Outcome |
| title | Impact of genetic polymorphisms on tacrolimus pharmacokinetics and the clinical outcome of renal transplantation |
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