ArticleCancer chemotherapy and pharmacology2025
Association of DPYD rs4294451, plasma uracil concentration, and sex with 5-fluorouracil exposure in patients with gastrointestinal cancer.
Article in Cancer chemotherapy and pharmacology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Metabolic Alterations in Blood and Saliva During the First Two Cycles of Adjuvant Chemotherapy Correlate with 5-FU Dose Reduction Requirement in Patients with Colorectal Cancer.European journal of drug metabolism and pharmacokinetics · 2026Article
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13 authors.
Funding
Abstract
purposeStandard dosing of infusional 5-FU results in subtherapeutic drug exposure for up to half of all patients. We evaluated plasma uracil concentration and DPYD rs4294451 genotype as candidate predictors of individual-level 5-FU exposure.
methodsWe conducted a prospective study of drug exposure in patients with gastrointestinal cancer receiving infusional 5-FU. Participants were evaluated by measurement of fasting pretreatment plasma uracil concentration, DPYD gene sequence (including genotyping of rs4294451) and 5-FU area under the curve (5-FU AUC). We used a linear mixed-effects model to evaluate the association of 5-FU AUC with uracil concentration and rs4294451 genotype, adjusting for cycle number, sex, serum creatinine, and 5-FU dose.
resultsThere were 29 evaluable participants with a median age of 64 years (range 41-81); nine (31%) were female. The median plasma uracil concentration was 10.4 ng/mL (IQR 7.2, 12.6). Nine participants carried the DPYD rs4294451 T-allele (7 with T/A, 2 with T/T.) Among all participants the median 5-FU AUC was 22.0 mg*h/L in cycle 1 and 19.3 mg*h/L in cycle 2. In the mixed-effects model, higher rs4294451 T-allele count (0, 1, or 2) was significantly associated with lower 5-FU AUC (-4.0 mg*h/L per T-allele [95% CI -8.0, 0.0], p = 0.049), as was male sex (-7.5 mg*h/L [95% CI -13.8, -1.3], p = 0.021). Pretreatment plasma uracil concentration was not significantly associated with 5-FU AUC (p = 0.57). The subject with the highest uracil concentration (23.1 ng/mL) had a rare DPYD missense variant (c.2185G > A [p.A729T]) and experienced early 5-FU-related toxicity.
conclusionsDPYD rs4294451 T-allele count and male sex were significantly associated with reduced 5-FU drug exposure. DPYD rs4294451 and male sex merit further evaluation as candidate biomarkers to inform initial dosing of infusional 5-FU.
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