Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype

H. Gurney, M. Wong, R. L. Balleine, L. P. Rivory, A. J. McLachlan, J. M. Hoskins, N. Wilcken, C. L. Clarke, G. J. Mann, M. Collins, S. E. Delforce, K. Lynch, H. Schran

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

LanguageEnglish
Pages33-40
Number of pages8
JournalClinical Pharmacology and Therapeutics
Volume82
Issue number1
DOIs
Publication statusPublished - 14 Jul 2007
Externally publishedYes

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P-Glycoprotein
Genotype
Cytochrome P-450 CYP3A
Gastrointestinal Stromal Tumors
Homozygote
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Thymidine
Single Nucleotide Polymorphism
Imatinib Mesylate
Pharmacokinetics
Phenotype
Pharmaceutical Preparations

Cite this

Gurney, H., Wong, M., Balleine, R. L., Rivory, L. P., McLachlan, A. J., Hoskins, J. M., ... Schran, H. (2007). Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clinical Pharmacology and Therapeutics, 82(1), 33-40. https://doi.org/10.1038/sj.clpt.6100201
Gurney, H. ; Wong, M. ; Balleine, R. L. ; Rivory, L. P. ; McLachlan, A. J. ; Hoskins, J. M. ; Wilcken, N. ; Clarke, C. L. ; Mann, G. J. ; Collins, M. ; Delforce, S. E. ; Lynch, K. ; Schran, H. / Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. In: Clinical Pharmacology and Therapeutics. 2007 ; Vol. 82, No. 1. pp. 33-40.
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abstract = "The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26{\%} at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.",
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Gurney, H, Wong, M, Balleine, RL, Rivory, LP, McLachlan, AJ, Hoskins, JM, Wilcken, N, Clarke, CL, Mann, GJ, Collins, M, Delforce, SE, Lynch, K & Schran, H 2007, 'Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype', Clinical Pharmacology and Therapeutics, vol. 82, no. 1, pp. 33-40. https://doi.org/10.1038/sj.clpt.6100201

Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. / Gurney, H.; Wong, M.; Balleine, R. L.; Rivory, L. P.; McLachlan, A. J.; Hoskins, J. M.; Wilcken, N.; Clarke, C. L.; Mann, G. J.; Collins, M.; Delforce, S. E.; Lynch, K.; Schran, H.

In: Clinical Pharmacology and Therapeutics, Vol. 82, No. 1, 14.07.2007, p. 33-40.

Research output: Contribution to journalArticleResearchpeer-review

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AU - McLachlan, A. J.

AU - Hoskins, J. M.

AU - Wilcken, N.

AU - Clarke, C. L.

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AU - Delforce, S. E.

AU - Lynch, K.

AU - Schran, H.

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N2 - The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

AB - The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.

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