Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0051771
Title: SLC22A1-ABCB1 Haplotype Profiles Predict Imatinib Pharmacokinetics in Asian Patients with Chronic Myeloid Leukemia
Authors: Singh O.
Chan J.Y.
Lin K.
Heng C.C.T.
Chowbay B. 
Keywords: breast cancer resistance protein
cytochrome P450 3A5
imatinib
multidrug resistance protein 1
organic cation transporter 1
pregnane X receptor
ABCB1 gene
ABCG2 gene
adult
aged
article
Asian
Chinese
chronic myeloid leukemia
clinical article
clinical trial
CYP3A5 gene
drug blood level
drug clearance
drug concentration
ethnic difference
female
gene linkage disequilibrium
gene sequence
genetic screening
haplotype
human
human experiment
Indian
Malay
male
normal human
nucleotide sequence
pharmacogenetics
plasma trough concentration
prospective study
PXR gene
Singapore
single nucleotide polymorphism
SLC22A1 gene
Adolescent
Adult
Aged
Antineoplastic Agents
Asian Continental Ancestry Group
Benzamides
Female
Haplotypes
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Linkage Disequilibrium
Malaysia
Male
Middle Aged
Organic Cation Transporter 1
P-Glycoprotein
Pharmacogenetics
Piperazines
Polymorphism, Single Nucleotide
Protein Kinase Inhibitors
Pyrimidines
Treatment Outcome
Young Adult
Issue Date: 2012
Citation: Singh O., Chan J.Y., Lin K., Heng C.C.T., Chowbay B. (2012). SLC22A1-ABCB1 Haplotype Profiles Predict Imatinib Pharmacokinetics in Asian Patients with Chronic Myeloid Leukemia. PLoS ONE 7 (12) : e51771. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0051771
Rights: Attribution 4.0 International
Abstract: Objective: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5*3 genetic polymorphisms on imatinib mesylate (IM) pharmacokinetics in Asian patients with chronic myeloid leukemia (CML). Patients and Methods: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each) and CML patients (n = 38) were enrolled in a prospective pharmacogenetics study. Imatinib trough (C0h) and clearance (CL) were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM) to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. Results: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T), to be significantly associated with IM clearance (p = 0.013). Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (*10-2 L/hr/mg): CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C0h than patients carrying 0 or 1 copy [CL (*10-2 L/hr/mg): 2.19 vs 3.29, p = 0.026; C0h (*10-6 1/ml): 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C0h (p = 0.002 and 0.009, respectively). Conclusion: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients. © 2012 Singh et al.
Source Title: PLoS ONE
URI: https://scholarbank.nus.edu.sg/handle/10635/161358
ISSN: 19326203
DOI: 10.1371/journal.pone.0051771
Rights: Attribution 4.0 International
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