{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:12:58Z","timestamp":1791475978557,"version":"4.3.4"},"reference-count":53,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2013,6,20]],"date-time":"2013-06-20T00:00:00Z","timestamp":1371686400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2013,7]]},"abstract":"Aims<\/jats:title>In children with acute lymphoblastic leukaemia (ALL<\/jats:styled-content>) bone marrow activity can influence red blood cell (RBC<\/jats:styled-content>) kinetics, the surrogate tissue for thiopurine methyltransferase (TPMT<\/jats:styled-content>) measurements. The aim of this study was to investigate TPMT<\/jats:styled-content> phenotype\u2013genotype concordance in ALL<\/jats:styled-content>, and the influence of TPMT<\/jats:styled-content> on thiopurine metabolite formation.<\/jats:p><\/jats:sec>Methods<\/jats:title>We measured TPMT<\/jats:styled-content> (activity, as units\u2009ml\u22121<\/jats:sup> packed RBCs<\/jats:styled-content> and genotype) at diagnosis (n<\/jats:italic> = 1150) and TPMT<\/jats:styled-content> and thioguanine nucleotide (TGN<\/jats:styled-content>) and methylmercaptopurine nucleotide (MeMPN<\/jats:styled-content>) metabolites (pmol\/8 \u00d7 108<\/jats:sup> RBCs<\/jats:styled-content>) during chemotherapy (n<\/jats:italic> = 1131) in children randomized to thioguanine or mercaptopurine on the U<\/jats:styled-content>nited K<\/jats:styled-content>ingdom trial ALL97<\/jats:styled-content>.<\/jats:p><\/jats:sec>Results<\/jats:title>Median TPMT<\/jats:styled-content> activity at diagnosis (8.5\u2009units) was significantly lower than during chemotherapy (13.8\u2009units, median difference 5.1\u2009units, 95% confidence interval (CI<\/jats:styled-content>) 4.8, 5.4, P<\/jats:italic> < 0.0001). At diagnosis genotype\u2013phenotype was discordant. During chemotherapy the overall concordance was 92%, but this fell to 55% in the intermediate activity cohort (45% had wild\u2010type genotypes). For both thiopurines TGN<\/jats:styled-content> concentrations differed by TPMT<\/jats:styled-content> status. For mercaptopurine, median TGNs<\/jats:styled-content> were higher in TPMT<\/jats:styled-content> heterozygous genotype (754\u2009pmol) than wild\u2010type (360\u2009pmol) patients (median difference 406\u2009pmol, 95% CI<\/jats:styled-content> 332, 478, P<\/jats:italic> < 0.0001), whilst median MeMPNs<\/jats:styled-content>, products of the TPMT<\/jats:styled-content> reaction, were higher in wild\u2010type (10\u2009650\u2009pmol) than heterozygous patients (3868\u2009pmol) (P<\/jats:italic> < 0.0001). In TPMT<\/jats:styled-content> intermediate activity patients with a wild\u2010type genotype, TGN<\/jats:styled-content> (median 366\u2009pmol) and MeMPN<\/jats:styled-content> (median 8590\u2009pmol) concentrations were similar to those in wild\u2010type, high activity patients.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>In childhood ALL<\/jats:styled-content>, TPMT<\/jats:styled-content> activity should not be used to predict heterozygosity particularly in blood samples obtained at disease diagnosis. Genotype is a better predictor of TGN<\/jats:styled-content> accumulation during chemotherapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.12066","type":"journal-article","created":{"date-parts":[[2012,12,18]],"date-time":"2012-12-18T20:28:05Z","timestamp":1355862485000},"page":"125-136","source":"Crossref","is-referenced-by-count":52,"title":["Thiopurine methyltransferase genotype\u2013phenotype discordance and thiopurine active metabolite formation in childhood acute lymphoblastic leukaemia"],"prefix":"10.1111","volume":"76","author":[{"given":"Lynne","family":"Lennard","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Unit Department of Human Metabolism University of Sheffield Sheffield S10\u20092RX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cher Suzanne","family":"Cartwright","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology Unit Department of Human Metabolism University of Sheffield Sheffield S10\u20092RX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Wade","sequence":"additional","affiliation":[{"name":"Clinical Trials Service Unit Oxford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M.","family":"Richards","sequence":"additional","affiliation":[{"name":"Clinical Trials Service Unit Oxford"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Vora","sequence":"additional","affiliation":[{"name":"Haematology Department The Children's Hospital Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,6,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401704"},{"key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"2311","DOI":"10.1182\/blood.V89.7.2311","article-title":"Randomized comparison of DAT versus ADE as induction therapy in children and younger adults with acute myeloid leukaemia. Results of the Medical Research Council's 10th AML Trial (MRC AML 10)","volume":"89","author":"Hann IM","year":"1997","journal-title":"Blood"},{"key":"e_1_2_9_4_1","first-page":"651","article-title":"Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity","volume":"32","author":"Weinshilboum RM","year":"1980","journal-title":"Am J Hum Genet"},{"key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.1182\/blood.V92.10.3569","article-title":"Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukaemia: a joint Children's Cancer Group and Pediatric Oncology Branch study","volume":"92","author":"Balis FM Holcenberg JS","year":"1998","journal-title":"Blood"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1989.119"},{"key":"e_1_2_9_7_1","first-page":"738","article-title":"A biochemical mechanism for the delayed cytotoxic reactions of 6\u2010mercaptopurine","volume":"34","author":"Tidd DM","year":"1974","journal-title":"Cancer Res"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/ldl020"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2008.07.026"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI16432"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.640"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1097\/FPC.0b013e3283449200"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)83063-X"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-911X(199710)29:4<252::AID-MPO3>3.0.CO;2-L"},{"key":"e_1_2_9_15_1","first-page":"441","article-title":"Severe 6\u2010thioguanine\u2010induced marrow aplasia in a child with acute lymphoblastic leukaemia and inherited thiopurine methyltransferase deficiency. J Pediatric Hematology","volume":"22","author":"McBride KL","year":"2000","journal-title":"Oncology"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(90)91745-V"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/91.23.2001"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.2009.069252"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2010.320"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.fpc.0000114745.08559.db"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9236(97)90152-1"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(06)69558-5"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2006.07.002"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2005.05509.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(94)00327-0"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0378-4347(92)80347-S"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0306-5251.2001.01497.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.1995.tb05776.x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1993.311"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0306-5251.2001.01391.x"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2004.10.027"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2710.2007.00858.x"},{"key":"e_1_2_9_33_1","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1182\/blood.V85.7.1897.bloodjournal8571897","article-title":"Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia","volume":"7","author":"McLeod HL","year":"1995","journal-title":"Blood"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1080\/15257770600890814"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-006-9119-z"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31816c20b3"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1097\/00008571-199510000-00003"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.2217\/pgs.09.103"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702152"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-154-12-201106210-00009"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1067\/mcp.2000.108674"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2005.053157"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1258\/acb.2008.008167"},{"key":"e_1_2_9_44_1","first-page":"470","article-title":"Mechanisms of action of thiopurines used in the curative therapy for childhood leukaemias","volume":"44","author":"Nelson JA","year":"1992","journal-title":"Cancer Bull"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.fpc.0000174788.69991.6b"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.04.032"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209372"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1995.450"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-911X(199802)30:2<85::AID-MPO3>3.0.CO;2-W"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.38.9924"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clpt.2003.12.001"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0b013e3282ffda37"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2010.03867.x"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1990.172"}],"container-title":["British Journal of Clinical Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fbcp.12066","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bcp.12066","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,3]],"date-time":"2023-10-03T14:59:34Z","timestamp":1696345174000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bcp.12066"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2013,6,20]]},"references-count":53,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2013,7]]}},"alternative-id":["10.1111\/bcp.12066"],"URL":"https:\/\/doi.org\/10.1111\/bcp.12066","archive":["Portico"],"relation":{},"ISSN":["0306-5251","1365-2125"],"issn-type":[{"value":"0306-5251","type":"print"},{"value":"1365-2125","type":"electronic"}],"subject":[],"published":{"date-parts":[[2013,6,20]]}}}