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01-07-2015 | Original Article

Influence of metastatic disease on the usefulness of uracil pharmacokinetics as a screening tool for DPD activity in colorectal cancer patients

Authors: Maurice C. van Staveren, Frans Opdam, Henk-Jan Guchelaar, André B. P. van Kuilenburg, Jan Gerard Maring, Hans Gelderblom

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2015

Abstract

Purpose

Dihydropyrimidine dehydrogenase (DPD) deficiency can lead to severe toxicity in patients treated with a standard dose of a fluoropyrimidine such as 5-fluorouracil or capecitabine (CAP). Administration of oral uracil and subsequent measurement of uracil and dihydrouracil (DHU) plasma concentrations has been used to identify patients with DPD deficiency. Liver metastasis might influence systemic DPD activity. The aim of the study was to investigate the effect of metastatic disease on the pharmacokinetics of uracil and DHU after oral administration of uracil.

Methods

500 mg/m² uracil was administered orally to 12 subjects with stages II–III colorectal cancer (CRC) who were treated in the adjuvant setting and to 12 subjects with stage IV metastasized CRC, all treated with CAP containing therapy. All subjects had a normal DPD activity defined as >6 nmol/mg/h determined in peripheral blood mononuclear cells.

Results

The mean uracil clearance [CL 51.7 (SD 6.4) vs. 46.7 (SD 13.0) l/h], area under the curve [AUC_0–220min 20.6 (SD 6.4) vs. 21.0 (SD 5.7) h mg/l], elimination half-life [t _1/2 21 (SD 7) vs. 21 (SD 8) min], maximum concentration time [T _max 27 (SD 9) vs. 25 (SD 9) min], volume of distribution [V 26.58 (SD 10.11) vs. 21.10 (SD 8.48) l] and the elimination constant [k _el 2.01 (SD 0.56) vs. 2.41 (SD 0.72) h⁻¹] did not differ significantly (p > 0.05) non-metastatic CRD versus metastatic CRC.

Conclusions

Metastasis does not alter uracil pharmacokinetics and is similar in CRC patients with and without metastasis. Therefore, the uracil test dose could be used as a DPD phenotype test in both adjuvantly treated and metastatic CRC patients using similar cutoff criteria to identify patients with DPD deficiency.

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Title: Influence of metastatic disease on the usefulness of uracil pharmacokinetics as a screening tool for DPD activity in colorectal cancer patients
Authors: Maurice C. van Staveren
Frans Opdam
Henk-Jan Guchelaar
André B. P. van Kuilenburg
Jan Gerard Maring
Hans Gelderblom
Publication date: 01-07-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 1/2015
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-015-2746-3

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