The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers
We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study...
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| Veröffentlicht in: | Clinical pharmacology and therapeutics 2007-03, Vol.81 (3), p.392-400 |
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| creator | Lévesque, E Delage, R Benoit‐Biancamano, M‐O Caron, P Bernard, O Couture, F Guillemette, C |
| description | We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no polymorphisms (controls) and 17 carriers of UGT1A9 —275/–2152 selected among 305 individuals genetically screened for UDP‐glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups included carriers of UGT1A8*2 (A173G) (n=9), UGT1A8*3 (C277Y) (n=4), and UGT1A9*3 (M33T) (n=5). Genetic analysis also included UGT2B7 to detect UGT2B7*2 (His268Tyr) and the promoter haplotype −1248A>G, −1241T>C, −1054T>C, −842G>A, −268A>G, −102T>C. Kinetics were measured in plasma and urine after a single 1.5 g oral dose of MMF, by high‐performance liquid chromatography coupled with tandem mass spectrometry, over 12 h after drug intake. Compared to controls, MPA exposure was significantly lower for UGT1A9 −275/−2152 carriers, with no significant changes in MPAG. The estimates of enterohepatic (re)cycling (area under the concentration–time curve (AUC6–12 h/AUC0–12 h)) were significantly lower for MPA, MPAG, and AcMPAG in UGT1A9 −275/−2152 subjects. Compared with controls, UGT1A9*3 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A8*2 allele and heterozygosity for UGT1A8*3 allele had no impact on MPA PKs. Compared with UGT2B7*1/*1 individuals (n=10), UGT2B7*2/*2 subjects (n=17) presented significantly higher free MPA Cmax values and elevated free and total MPA. Results indicate that after a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT1A8, UGT1A9, and UGT2B7 genes.
Clinical Pharmacology & Therapeutics (2007) 81, 392–400. doi:10.1038/sj.clpt.6100073 |
| doi_str_mv | 10.1038/sj.clpt.6100073 |
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Clinical Pharmacology & Therapeutics (2007) 81, 392–400. doi:10.1038/sj.clpt.6100073</description><identifier>ISSN: 0009-9236</identifier><identifier>EISSN: 1532-6535</identifier><identifier>DOI: 10.1038/sj.clpt.6100073</identifier><identifier>PMID: 17339869</identifier><identifier>CODEN: CLPTAT</identifier><language>eng</language><publisher>New York, NY: Nature Publishing</publisher><subject>Adolescent ; Adult ; Antibiotics, Antineoplastic - pharmacokinetics ; Area Under Curve ; Biological and medical sciences ; Biological Availability ; Biotransformation ; Cohort Studies ; Female ; Gene Frequency ; Glucuronosyltransferase - genetics ; Haplotypes ; Heterozygote ; Homozygote ; Humans ; Male ; Medical sciences ; Middle Aged ; Molecular Sequence Data ; Mycophenolic Acid - pharmacokinetics ; Pharmacology. Drug treatments ; Polymorphism, Genetic - physiology ; Reverse Transcriptase Polymerase Chain Reaction</subject><ispartof>Clinical pharmacology and therapeutics, 2007-03, Vol.81 (3), p.392-400</ispartof><rights>2007 American Society for Clinical Pharmacology and Therapeutics</rights><rights>2007 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4643-865cb52b07a0eba907f6855c759b1b5bba91b9af7967afc753a47d7841968cd23</citedby><cites>FETCH-LOGICAL-c4643-865cb52b07a0eba907f6855c759b1b5bba91b9af7967afc753a47d7841968cd23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1038%2Fsj.clpt.6100073$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1038%2Fsj.clpt.6100073$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18715691$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17339869$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lévesque, E</creatorcontrib><creatorcontrib>Delage, R</creatorcontrib><creatorcontrib>Benoit‐Biancamano, M‐O</creatorcontrib><creatorcontrib>Caron, P</creatorcontrib><creatorcontrib>Bernard, O</creatorcontrib><creatorcontrib>Couture, F</creatorcontrib><creatorcontrib>Guillemette, C</creatorcontrib><title>The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers</title><title>Clinical pharmacology and therapeutics</title><addtitle>Clin Pharmacol Ther</addtitle><description>We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no polymorphisms (controls) and 17 carriers of UGT1A9 —275/–2152 selected among 305 individuals genetically screened for UDP‐glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups included carriers of UGT1A8*2 (A173G) (n=9), UGT1A8*3 (C277Y) (n=4), and UGT1A9*3 (M33T) (n=5). Genetic analysis also included UGT2B7 to detect UGT2B7*2 (His268Tyr) and the promoter haplotype −1248A>G, −1241T>C, −1054T>C, −842G>A, −268A>G, −102T>C. Kinetics were measured in plasma and urine after a single 1.5 g oral dose of MMF, by high‐performance liquid chromatography coupled with tandem mass spectrometry, over 12 h after drug intake. Compared to controls, MPA exposure was significantly lower for UGT1A9 −275/−2152 carriers, with no significant changes in MPAG. The estimates of enterohepatic (re)cycling (area under the concentration–time curve (AUC6–12 h/AUC0–12 h)) were significantly lower for MPA, MPAG, and AcMPAG in UGT1A9 −275/−2152 subjects. Compared with controls, UGT1A9*3 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A8*2 allele and heterozygosity for UGT1A8*3 allele had no impact on MPA PKs. Compared with UGT2B7*1/*1 individuals (n=10), UGT2B7*2/*2 subjects (n=17) presented significantly higher free MPA Cmax values and elevated free and total MPA. Results indicate that after a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT1A8, UGT1A9, and UGT2B7 genes.
Clinical Pharmacology & Therapeutics (2007) 81, 392–400. doi:10.1038/sj.clpt.6100073</description><subject>Adolescent</subject><subject>Adult</subject><subject>Antibiotics, Antineoplastic - pharmacokinetics</subject><subject>Area Under Curve</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Biotransformation</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Gene Frequency</subject><subject>Glucuronosyltransferase - genetics</subject><subject>Haplotypes</subject><subject>Heterozygote</subject><subject>Homozygote</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Mycophenolic Acid - pharmacokinetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Polymorphism, Genetic - physiology</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><issn>0009-9236</issn><issn>1532-6535</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhS0EotPCmh3yBlbN1I7jv-UwwLRSUUdiyjZyHId4cOJgZ4TyOH1THE1Ql6yOffT53CsfAN5htMaIiJt4XGs3jGuGEUKcvAArTEmeMUroS7BKnsxkTtgFuIzxmK6FFOI1uMCcECmYXIGnQ2vgXTcoPULfwMfdAW_E9VnlNVR9PZ_zTxzuTG9Gq-Heu6nzYWht7CL0PRxTwr5VoVPa_7ILFHxjnZkjv03aD63pvUv-RtsabprRBKjgd9v_TMxDUA5-9tFA28Nbo9zYTvCHd6d-NCbEN-BVo1w0bxe9Ao9fvxy2t9n9w-5uu7nPdMEKkglGdUXzCnGFTKUk4g0TlGpOZYUrWiULV1I1XDKummQTVfCaiwJLJnSdkyvw8Zw7BP_7ZOJYdjZq45zqjT_FkqOcFJjO4M0Z1MHHGExTDsF2KkwlRuXcShmP5dxKubSSXrxfok9VZ-pnfqkhAR8WQEWtXBNUr2185gTHlEmcOH7m_qTPnf43t9zuD_9W-AtU9Kbu</recordid><startdate>200703</startdate><enddate>200703</enddate><creator>Lévesque, E</creator><creator>Delage, R</creator><creator>Benoit‐Biancamano, M‐O</creator><creator>Caron, P</creator><creator>Bernard, O</creator><creator>Couture, F</creator><creator>Guillemette, C</creator><general>Nature Publishing</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>7X8</scope></search><sort><creationdate>200703</creationdate><title>The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers</title><author>Lévesque, E ; Delage, R ; Benoit‐Biancamano, M‐O ; Caron, P ; Bernard, O ; Couture, F ; Guillemette, C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4643-865cb52b07a0eba907f6855c759b1b5bba91b9af7967afc753a47d7841968cd23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Antibiotics, Antineoplastic - pharmacokinetics</topic><topic>Area Under Curve</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Biotransformation</topic><topic>Cohort Studies</topic><topic>Female</topic><topic>Gene Frequency</topic><topic>Glucuronosyltransferase - genetics</topic><topic>Haplotypes</topic><topic>Heterozygote</topic><topic>Homozygote</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Mycophenolic Acid - pharmacokinetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Polymorphism, Genetic - physiology</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lévesque, E</creatorcontrib><creatorcontrib>Delage, R</creatorcontrib><creatorcontrib>Benoit‐Biancamano, M‐O</creatorcontrib><creatorcontrib>Caron, P</creatorcontrib><creatorcontrib>Bernard, O</creatorcontrib><creatorcontrib>Couture, F</creatorcontrib><creatorcontrib>Guillemette, C</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>MEDLINE - Academic</collection><jtitle>Clinical pharmacology and therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lévesque, E</au><au>Delage, R</au><au>Benoit‐Biancamano, M‐O</au><au>Caron, P</au><au>Bernard, O</au><au>Couture, F</au><au>Guillemette, C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers</atitle><jtitle>Clinical pharmacology and therapeutics</jtitle><addtitle>Clin Pharmacol Ther</addtitle><date>2007-03</date><risdate>2007</risdate><volume>81</volume><issue>3</issue><spage>392</spage><epage>400</epage><pages>392-400</pages><issn>0009-9236</issn><eissn>1532-6535</eissn><coden>CLPTAT</coden><abstract>We studied whether polymorphisms in the UGT1A8, UGT1A9, and UGT2B7 genes, the enzymes producing the phenolic (MPAG) and acyl (AcMPAG) glucuronides of mycophenolic acid (MPA), could contribute to the interindividual variation observed in mycophenolate mofetil (MMF) pharmacokinetics (PKs). This study enrolled 17 healthy volunteers with no polymorphisms (controls) and 17 carriers of UGT1A9 —275/–2152 selected among 305 individuals genetically screened for UDP‐glucuronosyltransferase (UGT) polymorphisms. Additional investigative groups included carriers of UGT1A8*2 (A173G) (n=9), UGT1A8*3 (C277Y) (n=4), and UGT1A9*3 (M33T) (n=5). Genetic analysis also included UGT2B7 to detect UGT2B7*2 (His268Tyr) and the promoter haplotype −1248A>G, −1241T>C, −1054T>C, −842G>A, −268A>G, −102T>C. Kinetics were measured in plasma and urine after a single 1.5 g oral dose of MMF, by high‐performance liquid chromatography coupled with tandem mass spectrometry, over 12 h after drug intake. Compared to controls, MPA exposure was significantly lower for UGT1A9 −275/−2152 carriers, with no significant changes in MPAG. The estimates of enterohepatic (re)cycling (area under the concentration–time curve (AUC6–12 h/AUC0–12 h)) were significantly lower for MPA, MPAG, and AcMPAG in UGT1A9 −275/−2152 subjects. Compared with controls, UGT1A9*3 carriers had higher MPA and AcMPAG exposure, whereas homozygosity for the UGT1A8*2 allele and heterozygosity for UGT1A8*3 allele had no impact on MPA PKs. Compared with UGT2B7*1/*1 individuals (n=10), UGT2B7*2/*2 subjects (n=17) presented significantly higher free MPA Cmax values and elevated free and total MPA. Results indicate that after a single oral dose of MMF in healthy volunteers, specific UGT genotypes significantly alter MPA PKs and this clearly warrants additional studies with complete and detailed genetic profiling of UGT1A8, UGT1A9, and UGT2B7 genes.
Clinical Pharmacology & Therapeutics (2007) 81, 392–400. doi:10.1038/sj.clpt.6100073</abstract><cop>New York, NY</cop><pub>Nature Publishing</pub><pmid>17339869</pmid><doi>10.1038/sj.clpt.6100073</doi><tpages>9</tpages></addata></record> |
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| ispartof | Clinical pharmacology and therapeutics, 2007-03, Vol.81 (3), p.392-400 |
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| subjects | Adolescent Adult Antibiotics, Antineoplastic - pharmacokinetics Area Under Curve Biological and medical sciences Biological Availability Biotransformation Cohort Studies Female Gene Frequency Glucuronosyltransferase - genetics Haplotypes Heterozygote Homozygote Humans Male Medical sciences Middle Aged Molecular Sequence Data Mycophenolic Acid - pharmacokinetics Pharmacology. Drug treatments Polymorphism, Genetic - physiology Reverse Transcriptase Polymerase Chain Reaction |
| title | The Impact of UGT1A8, UGT1A9, and UGT2B7 Genetic Polymorphisms on the Pharmacokinetic Profile of Mycophenolic Acid After a Single Oral Dose in Healthy Volunteers |
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