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Antimanic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Aman Upaganlawar, Abdulla Sherikar, Chandrashekhar Upasani
Tamoxifen is almost 100% bound to plasma protein. Tamoxifen undergoes biotransformation process through CYP2D6 and CYP 3A4/5 to 4-hydroxytamoxifen and N-desmethyltamoxifen, respectively, which are further metabolized into endoxifen. The half-life of tamoxifen is almost a week whereas N-desmethyltamoxifen is 14 days. Tamoxifen is removed from the body by both enterohepatic circulation (feces) and glomerular filtration (urine route) (Golan, 2012; Brunton et al., 2011; Katzung et al., 2009).
Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The main route of tamoxifen metabolism is through CYP3A4/5-mediated demethylation of the aminoethoxy side chain to N-desmethyltamoxifen (metabolite X) (Figure 3.96) (Lim et al. 1994; Mani et al. 1993a; Ruenitz et al. 1984), which has twice the half-life (approximately 14 days) as tamoxifen (approximately 5–7 days), and plasma levels are usually two- to threefold higher than those of tamoxifen (Jordan 1982). Chronic administration of 10 mg tamoxifen twice daily for 3 months to women results in average steady-state plasma concentrations of 120 ng/ml (range, 67–183 ng/ml) for tamoxifen and 336 ng/ml (range, 148–654 ng/ml) for N-desmethyltamoxifen (Jordan 1982). The average steady-state plasma concentrations of tamoxifen and N-desmethyltamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/ml (range, 71–183 ng/ml) and 353 ng/ml (range, 152–706 ng/ml), respectively (Soininen et al. 1986). N-Desmethyltamoxifen is further demethylated by CYP3A4/5 to N-desdimethyltamoxifen (metabolite Z) and then deaminated to metabolite Y (deam-ino-hydroxytamoxifen; tamoxifen-ol), a glycol derivative with antiestrogenic activity (Etienne et al. 1989; Fried and Wainer 1994; Langan-Fahey et al. 1990; Milano et al. 1987; Murphy et al. 1987). N-Desdimethyltamoxifen appears to be highly concentrated in the liver and is a potent inhibitor of certain CYPs including CYP3A (Comoglio et al. 1996), and this metabolite may mediate drug interactions involving tamoxifen, or it may modify tamoxifen-induced toxicity by inhibiting formation of CYP-catalyzed reactive metabolites from tamoxifen.
Chemoprevention of breast cancer with tamoxifen: recent experience and future perspectives
Published in A. R. Genazzani, Hormone Replacement Therapy and Cancer, 2020
B. Bonanni, A. Guerrieri-Gonzaga, N. Rotmensz, A. Decensi
There is indirect evidence that the risk of endometrial cancer induced by tamoxifen is both time- and dose-dependent, the higher relative risk being observed with daily doses of 40 or 30 mg/day of adjuvant tamoxifen27. One plausible way to lower this risk is therefore a reduction of the dose28. We therefore studied the biological activity of tamoxifen with a view to establishing a dosing schedule with a better risk-benefit ratio29,30. The blood concentrations of tamoxifen and its main metabolites were measured in a dose titration study in 105 healthy women (randomized to placebo, tamoxifen 10 mg on alternate days, 10 mg/day and 20 mg/day). Drug levels measured after 2 months of treatment were correlated with the changes in several biomarkers such as total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, lipoprotein (a), blood cell count, fibrinogen, antithrombin III, osteocalcin and IGF-I. Mean (±SD) tamoxifen and N-desmethyltamoxifen (metabolite X) concentrations were dose-related, being, respectively, 0 and 0 ng/ml with placebo, 26.8 ±15.1 and 43.7 ± 22.5 ng/ml with 10 mg every other day, 51.2 ±24.1 and 90.7 ±48 ng/ml with 10 mg/day, and 136 ±52.7 and 230.6 ± 75.0 ng/ml with 20 mg/day of tamoxifen. In contrast, the bio-marker changes were of comparable magnitudes at all drug concentrations, with the exception of platelet counts and triglyceride levels, both of which showed a trend towards increasing with increasing tamoxifen concentrations. A 75% reduction of the conventional dose, which resulted in an 80% decrease in serum drug concentration, did not affect tamoxifen activity on several bio-markers of cardiovascular and breast cancer risk and may in fact have a more favorable safety profile30.
Tamoxifen Never Ceases to Amaze: New Findings on Non-Estrogen Receptor Molecular Targets and Mediated Effects
Published in Cancer Investigation, 2018
Tatiana Anatolievna Bogush, Boris Borisovich Polezhaev, Ivan Andreevich Mamichev, Elena Alexandrovna Bogush, Boris Evseevich Polotsky, Sergei Alexeevich Tjulandin, Andrey Borisovich Ryabov
The interaction of tamoxifen with ceramides, which participate in cell cycle regulation in tumor cells and induce apoptosis, is actively explored in our days (43). Detailed information, concerning the mechanisms of ceramides effects and tamoxifen interaction with signaling pathways involving ceramides, was discussed in the review published in 2015 (44). In particular, tamoxifen effects on different steps of ceramide metabolism, associated with apoptosis induction, were demonstrated in different cancer cell cultures, including colon cancer, ovarian cancer, breast cancer, cervical cancer, prostate cancer and melanoma. The confirmation of the fact that this effect is not linked to tamoxifen's anti-estrogenic action, was obtained upon comparative estimation of tamoxifen and its metabolite, N-desmethyltamoxifen, which exhibits weak anti-estrogenic activity. It turned out, that in the later case the influence on ceramide metabolism was even more significant.