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.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-015-3452-x) contains supplementary material, which is available to authorized users.

Differences in the timing and magnitude ofPkd1gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of ADPKD

“…; Binkhorst et al. ). The plasma half‐life of tamoxifen and endoxifen in adult mice is 6–7 h after a single oral dose of 20–200 mg/kg tamoxifen; a 200 mg/kg dose is completely cleared of all bioactive forms within 2–3 days (Robinson et al.…”

Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

“…In contrast to food, the time of drug intake influences tamoxifen and endoxifen metabolism. Binkhorst and colleagues reported 15% and 3% higher endoxifen and tamoxifen systemic exposure (AUC 0-24 ) when tamoxifen was taken in the morning, whilst more balanced concentrations were found in the evening schedule [87]. Regardless of these differences, the authors concluded this phenomenon would probably not be clinically important for tamoxifen efficacy.…”

Candidate SNP Markers of Chronopathologies Are Predicted by a Significant Change in the Affinity of TATA-Binding Protein for Human Gene Promoters

“…Gene ESR2 codes for estrogen receptor 2 ( β ) and, in its promoter, contains a known SNP marker (rs35036378) for prophylactic treatment (with tamoxifen) of an ESR2-deficient primary tumor pT1 [ 87 ] to prevent progression to breast cancer [ 88 ]; this treatment is characterized by a circadian optimum for its use [ 89 ]. A keyword search yielded basic research findings of circadian disturbances of daytime behavioral activity in ESR2-deficient female mice [ 90 ].…”