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

• Published in: British journal of clinical pharmacology Vol. 82; no. 3; pp. 706 - 716
• Main Authors: Jacobs, Bart A. W., Deenen, Maarten J., Pluim, Dick, Hasselt, J. G. Coen, Krähenbühl, Martin D., Geel, Robin M. J. M., Vries, Niels, Rosing, Hilde, Meulendijks, Didier, Burylo, Artur M., Cats, Annemieke, Beijnen, Jos H., Huitema, Alwin D. R., Schellens, Jan H. M.
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 01.09.2016
• Subjects: 5‐fluorouracil; Adult; capecitabine; Circadian Rhythm; dihydropyrimidine dehydrogenase; Dihydrouracil Dehydrogenase (NADP) - genetics; Dihydrouracil Dehydrogenase (NADP) - metabolism; Female; Gene Expression - genetics; Healthy Volunteers; Humans; Leukocytes, Mononuclear - enzymology; Male; Middle Aged; Plasma - enzymology; Polymorphism, Genetic - genetics; thymidylate synthase; Thymidylate Synthase - genetics; Thymidylate Synthase - metabolism; Translational Research; Uracil - analogs & derivatives; Uracil - blood; Young Adult; 5-fluorouracil; capecitabine; thymidylate synthase; dihydropyrimidine dehydrogenase; circadian rhythm
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/bcp.13007

Aims 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. Methods 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. Results 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. Conclusions 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.