Back to Search
Start Over
Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers
- Source :
- British Journal of Clinical Pharmacology, 82(3), 706. NLM (Medline), British Journal of Clinical Pharmacology, 82(3), 706-716. Wiley
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Adult
Male
circadian rhythm
Gene Expression
thymidylate synthase
Biology
Pharmacology
Peripheral blood mononuclear cell
Thymidylate synthase
Capecitabine
03 medical and health sciences
chemistry.chemical_compound
Plasma
Young Adult
0302 clinical medicine
Translational Research
medicine
Dihydropyrimidine dehydrogenase
Humans
Pharmacology (medical)
5-fluorouracil
Circadian rhythm
Uracil
Dihydrouracil Dehydrogenase (NADP)
Polymorphism, Genetic
capecitabine
dihydropyrimidine dehydrogenase
Dihydrouracil
Middle Aged
Enzyme assay
Healthy Volunteers
030104 developmental biology
chemistry
030220 oncology & carcinogenesis
biology.protein
Leukocytes, Mononuclear
Female
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 03065251
- Database :
- OpenAIRE
- Journal :
- British Journal of Clinical Pharmacology, 82(3), 706. NLM (Medline), British Journal of Clinical Pharmacology, 82(3), 706-716. Wiley
- Accession number :
- edsair.doi.dedup.....8bbbd51bc304d99862cff6f924886bc5