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Pharmacokinetics and pharmacogenetics predict the inhibitory effects of tamoxifen on platelet aggregation
Author(s) -
Jin Y.,
Ward B.,
Bermes A.,
Storniolo A. M.,
Lemler S.,
Skaar T.,
Desta Z.,
Flockhart D. A.
Publication year - 2004
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2003.11.251
Subject(s) - tamoxifen , pharmacology , platelet , cyp2d6 , medicine , pharmacokinetics , pharmacogenomics , pharmacogenetics , chemistry , endocrinology , breast cancer , cancer , metabolism , biochemistry , gene , cytochrome p450 , genotype
Platelets play a central role in the pathogenesis of coronary artery disease. We tested ADP induced platelet aggregation with the Chrono‐Log® whole blood aggregometer before and after four months of tamoxifen treatment in women with breast cancer. Steady state plasma concentrations of tamoxifen and its metabolites, and common genetic variants, including eNOS, ER α and β, CYP 2D6, and 3A5 were also determined. There was a trend toward reduction in ADP induced platelet aggregation after 4 months of tamoxifen therapy (from 14.16 + 3.6 ohms to 11.5±4.1 ohms, P= 0.07). We stratified the subjects into two groups based on the inhibitory effects on platelets by tamoxifen: the “responders” showed ≥ 4ohms (14.5±8.4) and the “non‐responders” exhibited < 4 ohms (0.6±1.65) reduction in platelet aggregation (p=0.01 by 2‐tailed t ‐test). The responders had significantly lower plasma endoxifen (4‐OH‐N‐desmethyl tamoxifen) and 4‐OH tamoxifen concentrations (14.18±7.75 vs 48.22±7 ng/ml for endoxifen, P=0.006; 2.95±1.3 vs 5.8±0.9 ng/ml for 4_OH tamoxifen, p=0.01); and were more likely to carry an ER β variant allele. Plasma endoxifen concentration had the strongest correlation with the amplitude of platelet inhibition (Spearman r 2 =0.61, p=0.03). In conclusion, tamoxifen significantly inhibited platelet aggregation in certain individuals, and low concentrations of endoxifen and 4‐OH tamoxifen as well as ER β genetic variants appeared to predict these effects. Clinical Pharmacology & Therapeutics (2004) 75 , P67–P67; doi: 10.1016/j.clpt.2003.11.251