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

• 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
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-023-04584-x

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.