Effects of prednisone and genetic polymorphisms on etoposide disposition in children with acute lymphoblastic leukemia.
Etoposide is a substrate for P-glycoprotein, CYP3A4, CYP3A5, and UGT1A1. Glucocorticoids modulate CYP3A and P-glycoprotein in preclinical 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, 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 versus 29.2 mL/min/m2, P <.0001) than at week 54. The day 29 etoposide or catechol area under the curve (AUC) was correlated with neutropenia (P =.027 and P =.0008, respectively). The relationship 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 =.002) for all patients, and the CYP3A5 AA and GSTP1 AA genotypes predicted lower clearance in blacks (P =.02 and.03, respectively). The UGT1A1 6/6, VDR intron 8 GG, and VDR Fok 1 CC genotypes predicted higher week 54 clearance in blacks (P =.039,.036, and.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.
Kishi
Shinji
S
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, University of Tennessee, Memphis, TN 38105, USA.
Yang
Wenjian
W
Boureau
Benoit
B
Morand
Stanislas
S
Das
Soma
S
Chen
Peixian
P
Cook
Edwin H
EH
Rosner
Gary L
GL
Schuetz
Erin
E
Pui
Ching-Hon
CH
Relling
Mary V
MV
D001483:Base Sequence; D002648:Child; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005047:Etoposide / Q000493:pharmacokinetics*; D005260:Female; D019450:Genes, MDR; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics / Q000378:metabolism; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D011241:Prednisone / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism; D000099148:UGT1A1 Enzyme
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004273:DNA, Neoplasm; D005047:Etoposide; D014453:Glucuronosyltransferase; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; D011241:Prednisone; D018167:Receptors, Calcitriol; D000099148:UGT1A1 Enzyme; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; C510163:CYP3A4 protein, human; C496556:GSTP1 protein, human