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

• Published in: Cancer chemotherapy and pharmacology 2015-07, Vol.76 (1), p.47-52
• Main Authors: van Staveren, Maurice C., Opdam, Frans, Guchelaar, Henk-Jan, van Kuilenburg, André B. P., Maring, Jan Gerard, Gelderblom, Hans
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Cancer Research; Capecitabine; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - pathology; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Dihydropyrimidine Dehydrogenase Deficiency - blood; Dihydropyrimidine Dehydrogenase Deficiency - enzymology; Dihydrouracil Dehydrogenase (NADP) - blood; Fluorouracil - administration & dosage; Fluorouracil - analogs & derivatives; Humans; Medicine; Medicine & Public Health; Neoplasm Metastasis; Neoplasm Staging; Oncology; Organoplatinum Compounds - administration & dosage; Original Article; Pharmacology/Toxicology; Uracil - administration & dosage; Uracil - analogs & derivatives; Uracil - blood; Uracil - pharmacokinetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-015-2746-3

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/m 2 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.