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

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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 [AUC0–220min 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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Conflict of interest

All authors declare to have no conflict of interest.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Authors and Affiliations

  1. Department of Pharmacy, Treant Healthgroup, Location Scheper, Scheper Hospital Emmen, Boermarkeweg 60, 7824 AA, Emmen, The Netherlands

    Maurice C. van Staveren

  2. Department of Pharmacy and Clinical Pharmacy, Antoni van Leeuwenhoek Dutch Cancer Institute, Amsterdam, The Netherlands

    Frans Opdam

  3. Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands

    Henk-Jan Guchelaar

  4. Laboratory Genetic Metabolic Diseases, Academic Medical Center Amsterdam, Amsterdam, The Netherlands

    André B. P. van Kuilenburg

  5. Department of Pharmacy, Diaconessen Hospital Meppel and Bethesda Hospital Hoogeveen, Meppel, The Netherlands

    Jan Gerard Maring

  6. Department of Clinical Oncology, Leiden University Medical Center, Leiden, The Netherlands

    Hans Gelderblom

Authors
  1. Maurice C. van Staveren
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  2. Frans Opdam
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  3. Henk-Jan Guchelaar
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  4. André B. P. van Kuilenburg
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  5. Jan Gerard Maring
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  6. Hans Gelderblom
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Corresponding author

Correspondence to Maurice C. van Staveren.

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van Staveren, M.C., Opdam, F., Guchelaar, HJ. et al. Influence of metastatic disease on the usefulness of uracil pharmacokinetics as a screening tool for DPD activity in colorectal cancer patients. Cancer Chemother Pharmacol 76, 47–52 (2015). https://doi.org/10.1007/s00280-015-2746-3

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  • DOI: https://doi.org/10.1007/s00280-015-2746-3

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