A polymorphism in ABCA2 is associated with neutropenia induced by capecitabine in Japanese patients with colorectal cancer

A polymorphism in ABCA2 is associated with neutropenia induced by capecitabine in Japanese patients with colorectal cancer

Purpose Capecitabine is a prodrug that converts to 5-fluorouracil (5-FU) in three steps. A previous study showed that ABCA2 rs2271862 (C > T) and ABCG5 rs6720173 were associated with increased clearance of 5-FU and 5′-deoxy-5-fluorouridine, respectively, in Spanish patients with colorectal cancer...

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Bibliographic Details
Published in:Cancer chemotherapy and pharmacology Vol. 92; no. 6; pp. 465 - 474
Main Authors: Shibata, Yukitaka, Matsumoto, Natsumi, Murase, Remi, Kubota, Yutaro, Ishida, Hiroo, Shimada, Ken, Fujita, Ken-ichi
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-12-2023
Springer Nature B.V
Subjects:
5-Fluorouracil
ABC transporter
ABC transporters
Biomarkers
Cancer
Cancer Research
Cancer therapies
Colorectal cancer
Colorectal carcinoma
Gene polymorphism
Genes
Genetic diversity
Genotype & phenotype
High performance liquid chromatography
Liquid chromatography
Medicine
Medicine & Public Health
Metabolites
Metastases
Neutropenia
Oncology
Original Article
Oxaliplatin
Pharmacodynamics
Pharmacokinetics
Pharmacology/Toxicology
Polymorphism
Risk reduction
Toxicity
Japan
ABCA2
ABCG5
ABCB1
Pharmacokinetics
Capecitabine
Neutropenia
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Summary:Purpose Capecitabine is a prodrug that converts to 5-fluorouracil (5-FU) in three steps. A previous study showed that ABCA2 rs2271862 (C > T) and ABCG5 rs6720173 were associated with increased clearance of 5-FU and 5′-deoxy-5-fluorouridine, respectively, in Spanish patients with colorectal cancer (CRC) (Br J Clin Pharmacol 2021) and reported that ABCA2 rs2271862 was associated with decreased risk of capecitabine-induced neutropenia. Other studies have reported that ABCB1 rs1128503, rs2032592, and rs1045642 were associated with capecitabine-induced toxicity in Spanish CRC patients (Oncotarget 2015, Phamacogenomics 2010). Here, we prospectively examined the effects of ABC transporter genes polymorphisms on capecitabine pharmacokinetics and toxicity. Methods We enrolled patients with postoperative CRC treated with adjuvant capecitabine plus oxaliplatin (CapeOX) and patients with metastatic CRC receiving CapeOX. Pharmacokinetic analysis of the first capecitabine dose (1000 mg/m 2 ) was performed on day 1. We analyzed plasma concentrations of capecitabine and its three metabolites by high-performance liquid chromatography and ABC transporter genes polymorphisms using direct sequencing. Results Patients with ABCA2 rs2271862 T/T genotype had significantly lower area under the plasma concentration–time curve of capecitabine, but not of its metabolites, which were divided by the dose of the parent drug, than patients with C/C or C/T genotype ( P  = 0.0238). Frequency of ≥ grade 2 neutropenia was significantly lower in patients with ABCA2 rs2271862 T/T genotype ( P  = 0.00915). Polymorphisms in ABCG5 and ABCB1 were not associated with capecitabine pharmacokinetics and toxicity. Conclusions We found that ABCA2 polymorphism was significantly associated with systemic exposure to capecitabine and capecitabine-induced neutropenia in Japanese patients with CRC.
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ISSN:0344-5704
1432-0843
DOI:10.1007/s00280-023-04584-x