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Prepublished online as a Blood First Edition Paper on September 11, 2003; DOI 10.1182/blood-2003-06-2105. This Article Full Text (PDF) Supplemental Tables All Versions of this Article: 2003-06-2105v1 103/1/67    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kishi, S. Articles by Relling, M. V Search for Related Content PubMed PubMed Citation Articles by Kishi, S. Articles by Relling, M. V Social Bookmarking                   What's this? Submitted June 26, 2003 Accepted August 15, 2003 Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia Shinji Kishi, Wenjian Yang, Benoit Boureau, Stanislas Morand, Soma Das, Peixian Chen, Edwin H Cook, Gary L Rosner, Erin G Schuetz, Ching-Hon Pui, and Mary V Relling* Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennessee, Memphis, TN, USA Department of Hematology-Oncolgy, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Human Genetics, University of Chicago, Chicago, IL, USA Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA * Corresponding author; email: mary.relling{at}stjude.org. Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in pre-clinical models, but their effect on clinical etoposide disposition is unknown. We studied the pharmacokinetics of etoposide and its catechol metabolite in children with acute lymphoblastic leukemia (ALL), along with polymorphisms in CYP3A4, CYP3A5, MDR1, GSTP1, UGT1A1, and VDR. Plasma pharmacokinetics were assessed at day 29, after 1 month of prednisone (n=102), and at week 54, without prednisone (n=44). On day 29, etoposide clearance was higher (47.4 vs. 29.2 ml/min/m2, p <0.0001) than at week 54. The day 29 etoposide or catechol area-under-the-curve (AUC) was correlated with neutropenia (p=0.027 and p=0.0008, respectively). The relation between genotype and etoposide disposition differed by race and by prednisone use. The MDR1 exon 26 CC genotype predicted higher day 29 etoposide clearance (p=0.002) for all, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (p=0.02 and 0.03, respectively). The UGT1A1 6/6,VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (p=0.039, 0.036, and 0.052, respectively). The UGT1A1 6/6 genotype predicted lower catechol AUC. Prednisone strongly induces etoposide clearance, genetic polymorphisms may predict the constitutive and induced clearance of etoposide, and the relationship between genotype and phenotype differs by race. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. J. Yang, C. Cheng, W. Yang, D. Pei, X. Cao, Y. Fan, S. B. Pounds, G. Neale, L. R. Trevino, D. French, et al. Genome-wide Interrogation of Germline Genetic Variation Associated With Treatment Response in Childhood Acute Lymphoblastic Leukemia JAMA, January 28, 2009; 301(4): 393 - 403. [Abstract] [Full Text] [PDF] D. French, L. H. Hamilton, L. A. Mattano Jr, H. N. Sather, M. Devidas, J. B. Nachman, and M. V. Relling A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group Blood, May 1, 2008; 111(9): 4496 - 4499. 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