Dihydropyrimidine Dehydrogenase Deficiency, a Pharmacogenetic Syndrome Associated with Potentially Life-Threatening Toxicity Following 5-Fluorouracil Administration

Ezzeldin, Hany; Diasio, Robert B.

doi:10.3816/ccc.2004.n.018

Cited by 155 publications

(133 citation statements)

References 50 publications

Supporting

Mentioning

130

Contrasting

Order By: Relevance

“…The presence of DPD deficiency results in a reduced ability to metabolize and clear 5-FU, and the half-life of the drug, which is normally in the range of 10–15 minutes, can be markedly prolonged [63–71]. A pharmacogenetic autosomal recessive syndrome has been identified in which partial and/or compete deficiency in the DPD enzyme has been observed in 3–5% and 0.1% of the general population, respectively [67, 68, 72–75]. In this setting, patients experience excessive, severe toxicity in the form of myelosuppression, diarrhea and mucositis, and neurotoxicity.…”

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

“…These findings suggest that there must be factors other than DPD status that contribute to 5-FU metabolism and eventual 5-FU toxicity. It has been suggested that fewer than 50% of individuals who experience grade 3–4 toxicity have mutations in the DPD gene and/or have diminished DPD activity that would identify individuals with low 5-FU clearance [68, 72, 74]. It is now known that 5-FU clearance is a function of several factors in addition to DPD.…”

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

172

147

View full text Add to dashboard Cite

Purpose For over 50 years, 5-FU has played a critical role in the systemic chemotherapy of cancer patients. 5-FU serves as the main backbone of combination chemotherapy for patients with colorectal cancer (CRC) in both the adjuvant and metastatic disease settings. Herein, we review the current status of 5-FU therapeutic drug monitoring (TDM) and discuss its potential role in the clinical practice setting. Method PubMed and abstracts from the American Society of Clinical Oncology (ASCO) were searched up through September 2015 for clinical data relating to 5-FU TDM. Results 5-FU dosing has been typically determined by using body surface area (BSA). However, it is now well-established that BSA-based 5-FU dosing is correlated with a wide variation of 5-FU systemic exposure. Pharmacokinetic (PK) studies of 5-FU systemic exposure have shown a wide range of interpatient variation of 5-FU plasma drug levels. Over the past 30 years, increasing efforts have been placed on optimizing 5-FU dosing with the main goals of increasing antitumor efficacy while reducing drug-associated toxicity. There is growing evidence to show that 5-FU dosing based on plasma 5-FU drug level is feasible and that 5-FU TDM can improve clinical outcomes by improving efficacy of 5-FU-based combination regimens and reducing toxicities. Conclusion Dose adjustment of 5-FU is feasible and PK-based dosing can significantly improve clinical outcomes by reducing toxicities and improving efficacy.

show abstract

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

Section: Dihydropyrimidine Dehydrogenase (Dpd)mentioning

confidence: 99%

Therapeutic drug monitoring of 5-fluorouracil

Lee

Beumer

Chu

2016

Cancer Chemother Pharmacol

172

147

View full text Add to dashboard Cite

show abstract

“…Most of the dose is metabolized to 5-fluoro-deoxyuridine monophosphate (FdUMP), the active drug, by thymidine kinase [41]. In most patients, more than 85% of a 5-FU dose is inactivated by dihydropyrimidine dehydrogenase (DPD) [42]. Polymorphisms in genes that encode drugmetabolizing enzymes such as DPD might be clinically important if they have a reliable effect on enzyme activity and drug disposition (i.e., genotype can affect phenotype).…”

Section: Dihydropyrimidine Dehydrogenase Deficiencymentioning

confidence: 99%

“…Deficiency in DPD activity may reflect allelic variation in the DPYD (DihydroPYrimidine Dehydrogenase) gene that encodes the DPD enzyme [42]. However, there are 23 known allelic variants with varied relationships to DPD activity.…”

Section: Dihydropyrimidine Dehydrogenase Deficiencymentioning

confidence: 99%

“…In a study of 57 patients with head or neck cancer who received 5-day continuous intravenous infusions of 5-FU 1000 mg/m 2 /day, there was a linear correlation between DPD activity and 5-FU clearance [47]. Patients with the lowest DPD activity had the lowest 5-FU clearance and highest incidence of severe hematologic and gastrointestinal toxicities [42].…”

Section: Dihydropyrimidine Dehydrogenase Deficiencymentioning

confidence: 99%

See 1 more Smart Citation

Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

Alnaim¹

2010

SRX Pharmacology

View full text Add to dashboard Cite

Chemotherapeutic agents are generally characterized by a large inter-individual pharmacokinetic variability. The balance of efficacy and toxicity is critical and the imbalance can have devastating effects on patients. Standard dosing methods are inadequate in optimizing systemic exposure .Therapeutic drug monitoring (TDM) has the potential to improve the clinical use of chemotherapy agents. TDM has been successfully applied to optimize a few anticancer treatments including carboplatin, methotrexate, and 6-mercaptopurine. 5-Flurouracil (5-FU) is considered the backbone in treatments of advanced CRC. Toxic side effects remain a significant problem despite increased safety of newer regimens. Molecular mechanisms that control DPD-activity are complex and have not been fully elucidated and cannot be used effectively to individualize Fluorouracil dosing as there is no established standard genetic test for DPD deficiency. Current phenotypic methods to measure DPD-activity are cumbersome. A reliable relationship between DPD genotype and 5-FU toxicity phenotype has not been established. Standard dosing of 5FU is by body surface area (BSA). Low correlation exists between exposure and BSA. A better predictor of total exposure is the area under the curve (AUC). Toxicity and efficacy have been correlated to AUC with target of 24-30 (mg.h/l). The therapeutic window is very narrow and difficult to attain by clinical follow-up alone. TDM has been shown effective in adjusting the dose based on AUC.

show abstract

LC‐MS/MS method for simultaneous analysis of uracil, 5,6‐dihydrouracil, 5‐fluorouracil and 5‐fluoro‐5,6‐dihydrouracil in human plasma for therapeutic drug monitoring and toxicity prediction in cancer patients

Büchel

Rhyn

Schürch

et al. 2012

Biomedical Chromatography

View full text Add to dashboard Cite

The chemotherapeutic drug 5‐fluorouracil (5‐FU) is widely used for treating solid tumors. Response to 5‐FU treatment is variable with 10–30% of patients experiencing serious toxicity partly explained by reduced activity of dihydropyrimidine dehydrogenase (DPD). DPD converts endogenous uracil (U) into 5,6‐dihydrouracil (UH2), and analogously, 5‐FU into 5‐fluoro‐5,6‐dihydrouracil (5‐FUH2). Combined quantification of U and UH2 with 5‐FU and 5‐FUH2 may provide a pre‐therapeutic assessment of DPD activity and further guide drug dosing during therapy. Here, we report the development of a liquid chromatography–tandem mass spectrometry assay for simultaneous quantification of U, UH2, 5‐FU and 5‐FUH2 in human plasma. Samples were prepared by liquid–liquid extraction with 10:1 ethyl acetate‐2‐propanol (v/v). The evaporated samples were reconstituted in 0.1% formic acid and 10 μL aliquots were injected into the HPLC system. Analyte separation was achieved on an Atlantis dC18 column with a mobile phase consisting of 1.0 mm ammonium acetate, 0.5 mm formic acid and 3.3% methanol. Positively ionized analytes were detected by multiple reaction monitoring. The analytical response was linear in the range 0.01–10 μm for U, 0.1–10 μm for UH2, 0.1–75 μm for 5‐FU and 0.75–75 μm for 5‐FUH2, covering the expected concentration ranges in plasma. The method was validated following the FDA guidelines and applied to clinical samples obtained from ten 5‐FU‐treated colorectal cancer patients. The present method merges the analysis of 5‐FU pharmacokinetics and DPD activity into a single assay representing a valuable tool to improve the efficacy and safety of 5‐FU‐based chemotherapy. Copyright © 2012 John Wiley & Sons, Ltd.

show abstract

Dihydropyrimidine Dehydrogenase Deficiency, a Pharmacogenetic Syndrome Associated with Potentially Life-Threatening Toxicity Following 5-Fluorouracil Administration

Cited by 155 publications

References 50 publications

Therapeutic drug monitoring of 5-fluorouracil

Therapeutic drug monitoring of 5-fluorouracil

Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

LC‐MS/MS method for simultaneous analysis of uracil, 5,6‐dihydrouracil, 5‐fluorouracil and 5‐fluoro‐5,6‐dihydrouracil in human plasma for therapeutic drug monitoring and toxicity prediction in cancer patients

Contact Info

Product

Resources

About