Genetic influence of DPYD*9A polymorphism on plasma levels of 5-fluorouracil and subsequent toxicity after oral administration of capecitabine in colorectal cancer patients of South Indian origin

Objectives: High interindividual variability was reported with capecitabine toxicities among colorectal cancer (CRC) patients. DPYD*9A polymorphism was reported responsible for grade 3 or 4 toxicities. Finding the phenotypic association between DPYD*9A polymorphism and 5-fluorouracil (5-FU) plasma levels will give a better prediction for toxicity susceptibility.

Methods: A total of 145 CRC patients were included in the final analysis. Each patient received capecitabine of 1,000 mg/m² twice daily for the first 14 days of a 21 day cycle. 5-FU levels were measured at two-time points 2 and 3 h post capecitabine administration across the 1st and 4th cycles of chemotherapy. 5-FU levels were measured using liquid chromatography and tandem mass spectrometry (LC-MS/MS). Genotyping analysis was done by real-time PCR (RT-PCR).

Results: The mean 5-FU drug levels measured during the 1st cycle at time points 2 and 3 h were found to be 267 ng/mL ± (29) and 124 ng/mL ± (22) respectively. Whereas, the observed 5-FU levels in the 4th cycle were 275 ng/mL ± (28) and 130 ng/mL ± (26) respectively. Patients with 5-FU levels in the range of 281-320 and 141-160 ng/mL at 2 and 3 h respectively showed a higher risk for the hand-foot syndrome (HFS) and thrombocytopenia. No association was found between DPYD*9A polymorphism and 5-FU drug levels measured at time point 2 h across both the cycles. However, the drug levels measured at 3 h were found to be significantly different across the DPYD*9A genotypes. Individuals with GG genotype showed significantly higher 5-FU levels when compared to AA genotype.

Conclusions: DPYD*9A polymorphism had a significant influence on the plasma levels of 5-FU after capecitabine administration. The 5-FU levels measured at 3 h corresponding to elimination t_1/2 was significantly higher in patients with GG genotype compared AA genotype.