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Br J Clin Pharmacol. 2018 Dec;84(12):2761-2769. doi: 10.1111/bcp.13719. Epub 2018 Sep 25.

Food-effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers.

Author information

1
Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
2
Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
3
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
4
Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands.
5
Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
6
Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
7
Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
8
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands.
9
Department of Gastrointestinal Oncology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Abstract

AIMS:

This study aimed to determine the effect of food intake on uracil and dihydrouracil plasma levels. These levels are a promising marker for dihydropyrimidine dehydrogenase activity and for individualizing fluoropyrimidine anticancer therapy.

METHODS:

A randomized, cross-over study in 16 healthy volunteers was performed, in which subjects were examined in fasted and fed state on two separate days. In fed condition, a high-fat, high-caloric breakfast was consumed between 8:00 h and 8:30 h. Whole blood for determination of uracil, dihydrouracil and uridine plasma levels was drawn on both test days at predefined time points between 8:00 h and 13:00 h.

RESULTS:

Uracil levels were statistically significantly different between fasting and fed state. At 13:00 h, the mean uracil level in fasting state was 12.6 ± 3.7 ng ml-1 and after a test meal 9.4 ± 2.6 ng ml-1 (P < 0.001). Dihydrouracil levels were influenced by food intake as well (mean dihydrouracil level at 13:00 h in fasting state 147.0 ± 36.4 ng ml-1 and in fed state 85.7 ± 22.1 ng ml-1 , P < 0.001). Uridine plasma levels showed curves with similar patterns as for uracil.

CONCLUSIONS:

It was shown that both uracil and dihydrouracil levels were higher in fasting state than in fed state. This is hypothesized to be an direct effect of uridine plasma levels, which were previously shown to be elevated in fasting state and reduced after intake of food. These findings show that, when assessing plasma uracil and dihydrouracil levels for adaptive fluoropyrimidine dosing in clinical practice, sampling should be done between 8:00 h and 9:00 h after overnight fasting to avoid bias caused by circadian rhythm and food effects.

KEYWORDS:

dihydropyrimidine dehydrogenase; dihydrouracil; food-effect study; uracil; uridine

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