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ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia

The Pharmacogenomics Journal volume 18, pages 35–42 (2018)Cite this article

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Abstract

Neutropenia is a common dose-limiting toxicity associated with irinotecan treatment. Although UGT1A1 variants have been associated with neutropenia, a fraction of neutropenia risk remains unaccounted for. To identify additional genetic markers contributing to variability in irinotecan pharmacokinetics and neutropenia, a regression analysis was performed in 78 irinotecan-treated patients to analyze comprehensively three hepatic efflux transporter genes (ABCB1, ABCC1 and ABCG2). rs6498588 (ABCC1) and rs12720066 (ABCB1) were associated with increased SN-38 exposure, and rs17501331 (ABCC1) and rs12720066 were associated with lower absolute neutrophil count nadir. rs6498588 and a variant in high linkage disequilibrium are located in transcriptionally active regions or are predicted to alter transcription factor binding sites. While enhancer activity was not evident in vitro for genomic regions containing these single-nucleotide polymorphisms, rs6498588 was significantly associated with ABCC1 expression in human liver. These results suggest that genetic variation in ABCC1 and ABCB1 may contribute to irinotecan-induced neutropenia by altering expression of transporters involved in irinotecan metabolite disposition.

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Acknowledgements

This work was supported by NIH/NIGMS U01GM061390 (Pharmacogenetics of Membrane Transporters), NIH/NIGMS U01GM0061393 (PAAR-Pharmacogenomics of Anticancer Agents Research Group), NIH/NIGMS T32 GM007175, NIH/NIDDK R21DK081157 and NIH/NCI K07CA140390-01.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

    M Li, R M Baldwin & D L Kroetz

  2. Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    E L Seiser & F Innocenti

  3. Department of Medicine, The University of Chicago, Chicago, IL, USA

    J Ramirez & M J Ratain

  4. Institute for Human Genetics, University of California, San Francisco, CA, USA

    D L Kroetz

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  1. M Li
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Correspondence to D L Kroetz.

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Competing interests

Drs Innocenti and Ratain are patent holders on the UGT1A1 testing for irinotecan neutropenia. Dr Ratain also receives intermittent royalties on multiple patents related to irinotecan pharmacogenetics and is an inventor on a pending patent application for a genomic prescribing system. The remaining authors declare no conflict of interest.

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Li, M., Seiser, E., Baldwin, R. et al. ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia. Pharmacogenomics J 18, 35–42 (2018). https://doi.org/10.1038/tpj.2016.75

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