title: Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients.
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.
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. l.binkhorst@erasmusmc.nl.|Department of Hospital Pharmacy, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. l.binkhorst@erasmusmc.nl.
authors.forename: Lisette
authors.initials: L
authors.lastname: Binkhorst
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Jacqueline S L
authors.initials: JSL
authors.lastname: Kloth
authors.affiliation: Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Annelieke S
authors.initials: AS
authors.lastname: de Wit
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: de Bruijn
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Mei H
authors.initials: MH
authors.lastname: Lam
authors.affiliation: Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Ines
authors.initials: I
authors.lastname: Chaves
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Herman
authors.initials: H
authors.lastname: Burger
authors.affiliation: Department of Internal Medicine, TweeSteden Ziekenhuis, P.O. Box 90107, 5000 LA, Tilburg, Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: van Alphen
authors.affiliation: Department of Internal Medicine, Sint Franciscus Gasthuis, P.O. Box 10900, 3004 BA, Rotterdam, Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Hamberg
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Ron H N
authors.initials: RHN
authors.lastname: van Schaik
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Agnes
authors.initials: A
authors.lastname: Jager
authors.affiliation: Department of Hospital Pharmacy, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Birgit C P
authors.initials: BCP
authors.lastname: Koch
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Erik A C
authors.initials: EAC
authors.lastname: Wiemer
authors.affiliation: Department of Hospital Pharmacy, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.|Department of Internal Medicine, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.affiliation: Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands. g.vanderhorst@erasmusmc.nl.
authors.forename: Gijsbertus T J
authors.initials: GTJ
authors.lastname: van der Horst
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, P.O. Box 2040, 3000 CA, Rotterdam, Netherlands.
authors.forename: Ron H J
authors.initials: RHJ
authors.lastname: Mathijssen
mesh_terms: D000328:Adult; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D008875:Middle Aged; D010597:Pharmacogenetics; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics*; D013629:Tamoxifen / Q000493:pharmacokinetics*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System