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Breast Cancer Res Treat. 2015 Jul;152(1):119-128. doi: 10.1007/s10549-015-3452-x. Epub 2015 Jun 7.

Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients.

Author information

1
Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. l.binkhorst@erasmusmc.nl.
2
Department of Hospital Pharmacy, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. l.binkhorst@erasmusmc.nl.
3
Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
4
Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
5
Department of Internal Medicine, TweeSteden Ziekenhuis, P.O. Box 90107, 5000 LA, Tilburg, Netherlands.
6
Department of Internal Medicine, Sint Franciscus Gasthuis, P.O. Box 10900, 3004 BA, Rotterdam, Netherlands.
7
Department of Clinical Chemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
8
Department of Hospital Pharmacy, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
9
Department of Internal Medicine, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
10
Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. g.vanderhorst@erasmusmc.nl.

Abstract

The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen.

PMID:
26050156
PMCID:
PMC4469299
DOI:
10.1007/s10549-015-3452-x
[Indexed for MEDLINE]
Free PMC Article

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