Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation
Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes ( GSTA1 , GSTM1 , and GSTT1 ) on i.v. busulfan clearan...
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| Veröffentlicht in: | Biology of blood and marrow transplantation 2011-08, Vol.17 (8), p.1222-1230 |
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| creator | Kim, Sung-Doo Lee, Je-Hwan Hur, Eun-Hye Lee, Jung-Hee Kim, Dae-Young Lim, Sung-Nam Choi, Yunsuk Lim, Hyeong-Seok Bae, Kyun-Seop Noh, Gyu-Jeong Yun, Sung-Cheol Han, Sang Beom Lee, Kyoo-Hyung |
| description | Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes ( GSTA1 , GSTM1 , and GSTT1 ) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B ( P = .004), GSTM1/GSTT1 double-null genotype ( P = .039), and actual body weight ( P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1 - and GSTT- null genotypes, showed a significant correlation between GST genotype and busulfan clearance ( P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies. |
| doi_str_mv | 10.1016/j.bbmt.2010.12.708 |
| format | Article |
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We investigated the influence of polymorphisms of 3 GST isozyme genes ( GSTA1 , GSTM1 , and GSTT1 ) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B ( P = .004), GSTM1/GSTT1 double-null genotype ( P = .039), and actual body weight ( P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1 - and GSTT- null genotypes, showed a significant correlation between GST genotype and busulfan clearance ( P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.</description><identifier>ISSN: 1083-8791</identifier><identifier>EISSN: 1523-6536</identifier><identifier>DOI: 10.1016/j.bbmt.2010.12.708</identifier><identifier>PMID: 21215809</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Adult ; Alkylating Agents - administration & dosage ; Alkylating Agents - pharmacokinetics ; Busulfan ; Busulfan - administration & dosage ; Busulfan - pharmacokinetics ; Cyclophosphamide - administration & dosage ; Drug Administration Schedule ; Female ; Glutathione S-Transferase ; Glutathione Transferase - genetics ; Glutathione Transferase - metabolism ; Hematologic Neoplasms - drug therapy ; Hematologic Neoplasms - enzymology ; Hematologic Neoplasms - genetics ; Hematologic Neoplasms - surgery ; Hematology, Oncology and Palliative Medicine ; Hematopoietic cell transplantation ; Hematopoietic Stem Cell Transplantation - methods ; Humans ; Infusions, Intravenous ; Isoenzymes - genetics ; Isoenzymes - metabolism ; Male ; Middle Aged ; Pharmacogenetics ; Pharmacokinetics ; Polymorphism, Genetic ; Transplantation Conditioning - methods ; Vidarabine - administration & dosage ; Vidarabine - analogs & derivatives ; Young Adult</subject><ispartof>Biology of blood and marrow transplantation, 2011-08, Vol.17 (8), p.1222-1230</ispartof><rights>American Society for Blood and Marrow Transplantation</rights><rights>2011 American Society for Blood and Marrow Transplantation</rights><rights>Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-e4ec6baa7189acdb5f2fa55879820ec2b258ecefcb751760b1c5da0ae03950af3</citedby><cites>FETCH-LOGICAL-c520t-e4ec6baa7189acdb5f2fa55879820ec2b258ecefcb751760b1c5da0ae03950af3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S108387911001308X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3536,27902,27903,65308</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21215809$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Sung-Doo</creatorcontrib><creatorcontrib>Lee, Je-Hwan</creatorcontrib><creatorcontrib>Hur, Eun-Hye</creatorcontrib><creatorcontrib>Lee, Jung-Hee</creatorcontrib><creatorcontrib>Kim, Dae-Young</creatorcontrib><creatorcontrib>Lim, Sung-Nam</creatorcontrib><creatorcontrib>Choi, Yunsuk</creatorcontrib><creatorcontrib>Lim, Hyeong-Seok</creatorcontrib><creatorcontrib>Bae, Kyun-Seop</creatorcontrib><creatorcontrib>Noh, Gyu-Jeong</creatorcontrib><creatorcontrib>Yun, Sung-Cheol</creatorcontrib><creatorcontrib>Han, Sang Beom</creatorcontrib><creatorcontrib>Lee, Kyoo-Hyung</creatorcontrib><title>Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation</title><title>Biology of blood and marrow transplantation</title><addtitle>Biol Blood Marrow Transplant</addtitle><description>Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes ( GSTA1 , GSTM1 , and GSTT1 ) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B ( P = .004), GSTM1/GSTT1 double-null genotype ( P = .039), and actual body weight ( P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1 - and GSTT- null genotypes, showed a significant correlation between GST genotype and busulfan clearance ( P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Alkylating Agents - administration & dosage</subject><subject>Alkylating Agents - pharmacokinetics</subject><subject>Busulfan</subject><subject>Busulfan - administration & dosage</subject><subject>Busulfan - pharmacokinetics</subject><subject>Cyclophosphamide - administration & dosage</subject><subject>Drug Administration Schedule</subject><subject>Female</subject><subject>Glutathione S-Transferase</subject><subject>Glutathione Transferase - genetics</subject><subject>Glutathione Transferase - metabolism</subject><subject>Hematologic Neoplasms - drug therapy</subject><subject>Hematologic Neoplasms - enzymology</subject><subject>Hematologic Neoplasms - genetics</subject><subject>Hematologic Neoplasms - surgery</subject><subject>Hematology, Oncology and Palliative Medicine</subject><subject>Hematopoietic cell transplantation</subject><subject>Hematopoietic Stem Cell Transplantation - methods</subject><subject>Humans</subject><subject>Infusions, Intravenous</subject><subject>Isoenzymes - genetics</subject><subject>Isoenzymes - metabolism</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Pharmacogenetics</subject><subject>Pharmacokinetics</subject><subject>Polymorphism, Genetic</subject><subject>Transplantation Conditioning - methods</subject><subject>Vidarabine - administration & dosage</subject><subject>Vidarabine - analogs & derivatives</subject><subject>Young Adult</subject><issn>1083-8791</issn><issn>1523-6536</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9klFrFDEUhQdRbK3-AR8kbz7NepNpZjIgQl10u1Cw0C34FjKZO23WTDImmcL-B3-0GXb1wQefEsJ3Djn33KJ4S2FFgdYf9quuG9OKwfLAVg2IZ8U55awqa17Vz_MdRFWKpqVnxasY9wDQXIr2ZXHGKKNcQHte_Nq6wc7oNBI_kM3djmzQIbn19jD6MD2aOEbiHUmPSNYWVVAndOtSUE_o_BzJ5znOdlCOGEeu-tkmcquSQZciuXc9hgdv3AO5xlElP3mDyWiyRmvJLtvFySqXMu_d6-LFoGzEN6fzorj_-mW3vi5vvm2266ubUnMGqcRL1HWnVENFq3Tf8YENivMcVDBAzTrGBWocdNdw2tTQUc17BQqhajmooboo3h99p-B_zhiTHE3U-UPKYc4jRSOAtbxlmWRHUgcfY8BBTsGMKhwkBbmUIPdyKUEuJUjKZC4hi96d7OduxP6v5M_UM_DxCGAO-WQwyKjN0kFvAuoke2_-7__pH7m2xhmt7A88YNz7Obg8PkllZBLk3bIGyxZQAFqB-F79BhUpsKM</recordid><startdate>20110801</startdate><enddate>20110801</enddate><creator>Kim, Sung-Doo</creator><creator>Lee, Je-Hwan</creator><creator>Hur, Eun-Hye</creator><creator>Lee, Jung-Hee</creator><creator>Kim, Dae-Young</creator><creator>Lim, Sung-Nam</creator><creator>Choi, Yunsuk</creator><creator>Lim, Hyeong-Seok</creator><creator>Bae, Kyun-Seop</creator><creator>Noh, Gyu-Jeong</creator><creator>Yun, Sung-Cheol</creator><creator>Han, Sang Beom</creator><creator>Lee, Kyoo-Hyung</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>20110801</creationdate><title>Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation</title><author>Kim, Sung-Doo ; Lee, Je-Hwan ; Hur, Eun-Hye ; Lee, Jung-Hee ; Kim, Dae-Young ; Lim, Sung-Nam ; Choi, Yunsuk ; Lim, Hyeong-Seok ; Bae, Kyun-Seop ; Noh, Gyu-Jeong ; Yun, Sung-Cheol ; Han, Sang Beom ; Lee, Kyoo-Hyung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c520t-e4ec6baa7189acdb5f2fa55879820ec2b258ecefcb751760b1c5da0ae03950af3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Alkylating Agents - administration & dosage</topic><topic>Alkylating Agents - pharmacokinetics</topic><topic>Busulfan</topic><topic>Busulfan - administration & dosage</topic><topic>Busulfan - pharmacokinetics</topic><topic>Cyclophosphamide - administration & dosage</topic><topic>Drug Administration Schedule</topic><topic>Female</topic><topic>Glutathione S-Transferase</topic><topic>Glutathione Transferase - genetics</topic><topic>Glutathione Transferase - metabolism</topic><topic>Hematologic Neoplasms - drug therapy</topic><topic>Hematologic Neoplasms - enzymology</topic><topic>Hematologic Neoplasms - genetics</topic><topic>Hematologic Neoplasms - surgery</topic><topic>Hematology, Oncology and Palliative Medicine</topic><topic>Hematopoietic cell transplantation</topic><topic>Hematopoietic Stem Cell Transplantation - methods</topic><topic>Humans</topic><topic>Infusions, Intravenous</topic><topic>Isoenzymes - genetics</topic><topic>Isoenzymes - metabolism</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Pharmacogenetics</topic><topic>Pharmacokinetics</topic><topic>Polymorphism, Genetic</topic><topic>Transplantation Conditioning - methods</topic><topic>Vidarabine - administration & dosage</topic><topic>Vidarabine - analogs & derivatives</topic><topic>Young Adult</topic><toplevel>online_resources</toplevel><creatorcontrib>Kim, Sung-Doo</creatorcontrib><creatorcontrib>Lee, Je-Hwan</creatorcontrib><creatorcontrib>Hur, Eun-Hye</creatorcontrib><creatorcontrib>Lee, Jung-Hee</creatorcontrib><creatorcontrib>Kim, Dae-Young</creatorcontrib><creatorcontrib>Lim, Sung-Nam</creatorcontrib><creatorcontrib>Choi, Yunsuk</creatorcontrib><creatorcontrib>Lim, Hyeong-Seok</creatorcontrib><creatorcontrib>Bae, Kyun-Seop</creatorcontrib><creatorcontrib>Noh, Gyu-Jeong</creatorcontrib><creatorcontrib>Yun, Sung-Cheol</creatorcontrib><creatorcontrib>Han, Sang Beom</creatorcontrib><creatorcontrib>Lee, Kyoo-Hyung</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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>Biology of blood and marrow transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Sung-Doo</au><au>Lee, Je-Hwan</au><au>Hur, Eun-Hye</au><au>Lee, Jung-Hee</au><au>Kim, Dae-Young</au><au>Lim, Sung-Nam</au><au>Choi, Yunsuk</au><au>Lim, Hyeong-Seok</au><au>Bae, Kyun-Seop</au><au>Noh, Gyu-Jeong</au><au>Yun, Sung-Cheol</au><au>Han, Sang Beom</au><au>Lee, Kyoo-Hyung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation</atitle><jtitle>Biology of blood and marrow transplantation</jtitle><addtitle>Biol Blood Marrow Transplant</addtitle><date>2011-08-01</date><risdate>2011</risdate><volume>17</volume><issue>8</issue><spage>1222</spage><epage>1230</epage><pages>1222-1230</pages><issn>1083-8791</issn><eissn>1523-6536</eissn><abstract>Intravenous (i.v.) busulfan can produce a more consistent pharmacokinetic profile than oral formulations can, but nonetheless, significant interpatient variability is evident. We investigated the influence of polymorphisms of 3 GST isozyme genes ( GSTA1 , GSTM1 , and GSTT1 ) on i.v. busulfan clearance. Fifty-eight adult patients who received 3.2 mg/kg/day of busulfan as conditioning for hematopoietic cell transplantation were included in this study. Stepwise multiple linear regression demonstrated that GSTA1 variant GSTA1∗B ( P = .004), GSTM1/GSTT1 double-null genotype ( P = .039), and actual body weight ( P = .001) were significantly associated with lower clearance of i.v. busulfan. A trend test analyzing the overall effect of GST genotype on busulfan pharmacokinetics, combining GSTA1 gene polymorphism and the number of GSTM1 - and GSTT- null genotypes, showed a significant correlation between GST genotype and busulfan clearance ( P = .001). The clearance of i.v. busulfan was similar between patients with GSTA1∗A/∗A and GSTM1/GSTT1 double-null genotypes and those with GSTA1∗A/∗B and GSTM1/GSTT1 double-positive genotypes. In conclusion, a pharmacogenetic approach using GST gene polymorphisms may be valuable in optimizing the i.v. busulfan dosage scheme. Our results also highlight the importance of including polygenic analyses and addressing interactions among isozyme genes in pharmacogenetic studies.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>21215809</pmid><doi>10.1016/j.bbmt.2010.12.708</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Adolescent Adult Alkylating Agents - administration & dosage Alkylating Agents - pharmacokinetics Busulfan Busulfan - administration & dosage Busulfan - pharmacokinetics Cyclophosphamide - administration & dosage Drug Administration Schedule Female Glutathione S-Transferase Glutathione Transferase - genetics Glutathione Transferase - metabolism Hematologic Neoplasms - drug therapy Hematologic Neoplasms - enzymology Hematologic Neoplasms - genetics Hematologic Neoplasms - surgery Hematology, Oncology and Palliative Medicine Hematopoietic cell transplantation Hematopoietic Stem Cell Transplantation - methods Humans Infusions, Intravenous Isoenzymes - genetics Isoenzymes - metabolism Male Middle Aged Pharmacogenetics Pharmacokinetics Polymorphism, Genetic Transplantation Conditioning - methods Vidarabine - administration & dosage Vidarabine - analogs & derivatives Young Adult |
| title | Influence of GST Gene Polymorphisms on the Clearance of Intravenous Busulfan in Adult Patients Undergoing Hematopoietic Cell Transplantation |
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