Abstract
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. A total of 145 CRC patients were included in the final analysis. Each patient received capecitabine of 1,000mg/m2 twice daily for the first 14days of a 21day cycle. 5-FU levels were measured at two-time points 2 and 3h 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). The mean 5-FU drug levels measured during the 1st cycle at time points 2 and 3h were found to be 267ng/mL±(29) and 124ng/mL±(22) respectively. Whereas, the observed 5-FU levels in the 4th cycle were 275ng/mL±(28) and 130ng/mL±(26) respectively. Patients with 5-FU levels in the range of 281-320 and 141-160ng/mL at 2 and 3h 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 2h across both the cycles. However, the drug levels measured at 3h 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. DPYD*9A polymorphism had a significant influence on the plasma levels of 5-FU after capecitabine administration. The 5-FU levels measured at 3h corresponding to elimination t1/2 was significantly higher in patients with GG genotype compared AA genotype.
Highlights
Capecitabine is an oral prodrug and is converted to an active metabolite, 5-fluorouracil (5-FU) with the help of thymidine phosphorylase (TP) enzyme
We aimed to find the phenotypic association between dihydropyrimidine dehydrogenase (DPYD)*9A polymorphism and 5-FU drug levels after oral administration of capecitabine in colorectal cancer (CRC) patients of South Indian origin
We found a significant difference between DPYD*9A genotypes and 5-FU levels measured at time point 3 h in both the CAPOX chemotherapy cycles
Summary
Capecitabine is an oral prodrug and is converted to an active metabolite, 5-fluorouracil (5-FU) with the help of thymidine phosphorylase (TP) enzyme. The enzyme was found in higher levels in tumour cells when compared to normal healthy tissue. This explains the preferential activation of capecitabine and for 3–4 fold higher levels of 5-FU in the tumour cells when compared to adjacent healthy tissue [1]. Capecitabine exerts its chemotherapeutic activity in several ways. The main mechanism of action is by inhibition of thymidylate synthase (TYMS) enzyme, which plays an important role in the folate homocysteine cycle and pyrimidine synthesis pathways. The active metabolite (5-FU) can be incorporated directly into the RNA and DNA leading to cell death [2]
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