title: ABC transporter polymorphisms are associated with irinotecan pharmacokinetics and neutropenia.
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.
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: E L
authors.initials: EL
authors.lastname: Seiser
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Baldwin
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ramirez
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ratain
authors.affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: F
authors.initials: F
authors.lastname: Innocenti
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.|Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Kroetz
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000368:Aged; D005260:Female; D005838:Genotype; D006801:Humans; D000077146:Irinotecan / Q000493:pharmacokinetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics; D009503:Neutropenia / Q000235:genetics* / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D009363:Neoplasm Proteins; D000077146:Irinotecan