Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers

Bart A. W. Jacobs, Maarten J. Deenen, Dick Pluim, J. G. Coen van Hasselt, Martin D. Krahenbuhl, Robin M. J. M. van Geel, Niels de Vries, Hilde Rosing, Didier Meulendijks, Artur M. Burylo, Annemieke Cats, Jos H. Beijnen, Alwin D. R. Huitema, Jan H. M. Schellens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, we explored between-subject variability (BSV) and circadian rhythmicity in DPD and TS activity in human volunteers.The BSVs in DPD activity (n = 20) in peripheral blood mononuclear cells (PBMCs) and in plasma, measured by means of the dihydrouracil (DHU) and uracil (U) plasma levels and DHU : U ratio (n = 40), and TS activity in PBMCs (n = 19), were examined. Samples were collected every 4 h throughout 1 day for assessment of circadian rhythmicity in DPD and TS activity in PBMCs (n = 12) and DHU : U plasma ratios (n = 23). In addition, the effects of genetic polymorphisms and gene expression on DPD and TS activity were explored.Population mean (? standard deviation) DPD activity in PBMCs and DHU : U plasma ratio were 9.2 (?2.1) nmol mg(-1) h(-1) and 10.6 (?2.4), respectively. Individual TS activity in PBMCs ranged from 0.024 nmol mg(-1) h(-1) to 0.596 nmol mg(-1) h(-1) . Circadian rhythmicity was demonstrated for all phenotype markers. Between 00:30 h and 02:00 h, DPD activity in PBMCs peaked, while the DHU : U plasma ratio and TS activity in PBMCs showed trough activity. Peak-to-trough ratios for DPD and TS activity in PBMCs were 1.69 and 1.62, respectively. For the DHU : U plasma ratio, the peak-to-trough ratio was 1.43.BSV and circadian variability in DPD and TS activity were demonstrated. Circadian rhythmicity in DPD might be tissue dependent. The results suggested an influence of circadian rhythms on phenotype-guided fluoropyrimidine dosing and supported implications for chronotherapy with high-dose fluoropyrimidine administration during the night.? 2016 The British Pharmacological Society.
Original languageEnglish
Pages (from-to)706-716
JournalBritish Journal of Clinical Pharmacology
Volume82
Issue number3
DOIs
Publication statusPublished - Sep 2016

Keywords

  • 5-fluorouracil
  • capecitabine
  • circadian rhythm
  • dihydropyrimidine dehydrogenase
  • thymidylate synthase

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