DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report

Abstract

5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas.

Keywords: 5-fluorouracil; DPYD; dihydropyrimidine dehydrogenase; fluoropyrimidine; orthotopic liver transplant; therapeutic drug monitoring.

Figure 1

A simplified metabolism of 5-fluorouracil (5-FU). Thymidylate phosphorylase (TYMP) generates fluorouridine (FUDR), which is converted to Fluoro-deoxyuridine monophosphate (FdUMP) by thymidylate kinase (TYMK). FdUMP inhibits thymidylate synthase (TYMS) causing an imbalance of deoxyuridine monophosphate (dUMP) and deoxythymidine monophosphate (dTMP). Incorporation of dUMP into DNA causes damage and leads to cell death. 5-FU is converted to fluorouridine monophosphate (FUMP) by uridine monophosphate synthetase (UMPS) with further phosphorylation by uridine kinase (UK). Incorporation of fluorinated nucleotides (FUTP or FdUMP) into both RNA and DNA respectively leads to cell death. Inactivation of 5-FU occurs through dihydropyrimidine dehydrogenase (DPD) conversion to 5-dihydrofluorouracil (5-DHFU). Dihydropyrmidinase (DPYS) catalyzes the creation of fluoro-beta-ureidopropionate (FUPA) and beta-ureidopropionase (UPB1) activity culminates in urinary elimination of fluoro-beta-alanine (FBAL).