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

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Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada
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Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada
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Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada
*
Author to whom correspondence should be addressed.
Pharmaceutics 2019, 11(5), 199; https://doi.org/10.3390/pharmaceutics11050199
Received: 2 April 2019 / Revised: 19 April 2019 / Accepted: 23 April 2019 / Published: 1 May 2019
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. View Full-Text
Keywords: dihydropyrimidine dehydrogenase; DPYD; 5-fluorouracil; fluoropyrimidine; therapeutic drug monitoring; orthotopic liver transplant dihydropyrimidine dehydrogenase; DPYD; 5-fluorouracil; fluoropyrimidine; therapeutic drug monitoring; orthotopic liver transplant
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Wigle, T.J.; Tsvetkova, E.V.; Welch, S.A.; Kim, R.B. DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report. Pharmaceutics 2019, 11, 199.

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