The impact of liver resection on the dihydrouracil:uracil plasma ratio in patients with colorectal liver metastases

  • Eur J Clin Pharmacol. 2018 Jun;74(6):737-744. doi: 10.1007/s00228-018-2426-4.
Bart A W Jacobs  1  2 ,  Nikol Snoeren  3 ,  Morsal Samim  3 ,  Hilde Rosing  2 ,  Niels de Vries  2 ,  Maarten J Deenen  1 ,  Jos H Beijnen  2  4 ,  Jan H M Schellens  1  4 ,  Miriam Koopman  5 ,  Richard van Hillegersberg  6
Affiliations
  • 1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
  • 2. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands.
  • 3. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
  • 4. Science Faculty, Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, P.O. Box 80082, 3508 TB, Utrecht, The Netherlands.
  • 5. Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
  • 6. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. [email protected].
PMID: 29430582 DOI: 10.1007/s00228-018-2426-4
Abstract

Purpose: The dihydrouracil (DHU):uracil (U) plasma ratio is a promising marker for identification of dihydropyrimidine dehydrogenase (DPD)-deficient patients. The objective of this study was to determine the effect of liver resection on the DHU:U plasma ratio in patients with colorectal liver metastases (CRLM).

Methods: An observational study was performed in which DHU:U plasma ratios in patients with CRLM were analyzed prior to and 1 day after liver resection. In addition, the DHU:U plasma ratio was quantified in six additional patients 4-8 weeks after liver resection to explore long-term effects on the DHU:U plasma ratio. Quantification of U and DHU plasma levels was performed using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay.

Results: The median (range) DHU:U plasma ratio in 15 patients prior to liver resection was 10.7 (2.6-14.4) and was significantly reduced to 5.5 (< quantification limit (LLOQ-10.5) 1 day after resection (p = 0.0026). This reduction was caused by a decrease in DHU plasma levels from 112.0 (79.8-153) ng/mL to 41.2 (< LLOQ-160) ng/mL 1 day after resection (p = 0.0004). Recovery of the DHU:U plasma ratio occurred 4-8 weeks after liver resection, which was shown by a median (range) DHU:U plasma ratio in six patients of 9.1 (6.9-14.5).

Conclusion: Liver resection leads to very low DHU:U plasma ratios 1 day after liver resection, which is possibly caused by a reduction in DPD activity. Quantification of the DHU:U plasma ratios directly after liver resection could lead to false-positive identification of DPD deficiency and is therefore not advised.

Keywords
5-Fluorouracil; Capecitabine; Dihydropyrimidine dehydrogenase; Dihydrouracil; Liver resection; Uracil.
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