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

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

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.

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Acknowledgements

We would like to thank all the patients who participated in this study.

Funding

This work was supported by the Dutch Colorectal Cancer Group, University Medical Center Utrecht and The Netherlands Cancer Institute.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Bart A. W. Jacobs, Maarten J. Deenen & Jan H. M. Schellens

  2. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    Bart A. W. Jacobs, Hilde Rosing, Niels de Vries & Jos H. Beijnen

  3. Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Nikol Snoeren, Morsal Samim & Richard van Hillegersberg

  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

    Jos H. Beijnen & Jan H. M. Schellens

  5. Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

    Miriam Koopman

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  1. Bart A. W. Jacobs
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Correspondence to Richard van Hillegersberg.

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Jacobs, B.A.W., Snoeren, N., Samim, M. et al. The impact of liver resection on the dihydrouracil:uracil plasma ratio in patients with colorectal liver metastases. Eur J Clin Pharmacol 74, 737–744 (2018). https://doi.org/10.1007/s00228-018-2426-4

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  • DOI: https://doi.org/10.1007/s00228-018-2426-4

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