caa a22 4500 475818504 CHVBK 20180406123815.0 cr unu---uuuuu 170329e20000901xx s 000 0 eng 10.1007/s002280000176 doi (NATIONALLICENCE)springer-10.1007/s002280000176 Pharmacokinetics of (deaminohydroxy)toremifene in humans: a new, selective estrogen-receptor modulator [Elektronische Daten] [M. W. DeGregorio, G. T. Wurz, T. L. Taras, R. U. Erkkola, K. H. Halonen, R. K. Huupponen] Purpose: New selective estrogen-receptor modulators for the treatment and prevention of osteoporosis, cardiovascular disease and breast cancer are currently the focus of intense research. (Deaminohydroxy)toremifene (Z-2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]ethanol; FC-1271a) has been shown to prevent bone resorption in rats while having no or weak estrogen-like effects on the uterus, which makes it a good candidate drug for osteoporosis prevention. Our purpose here was to examine the pharmacokinetics of (deaminohydroxy)toremifene in humans included in two phase-I studies. Methods: The first was a single-dose, dose-escalation study with 28 healthy male volunteers. Doses ranged from 10 mg to 800 mg. The second study was conducted during a 12-week period with 40 healthy, post-menopausal women, who received repeated oral doses of 25-200 mg. Standard pharmacokinetic parameters were assessed. Results: In the single-dose study, time to reach peak concentration (tmax) ranged from 1.3 h to 4.0 h; peak concentration (Cmax) ranged from 15 ng/ml to 445 ng/ml; and the estimated terminal elimination half-life (mean ± SD; t1/2) was 24.8 ± 7.0 h. In the repeated-dose study, tmax ranged from 1.9 h to 2.6 h at 6 weeks and from 2.5 h to 2.9 h at 12 weeks. Cmax ranged from 295 ng/ml to 1043 ng/ml at 6 weeks and from 25 ng/ml to 1211 ng/ml at 12 weeks. The average t1/2 at all dose levels was 29.7 ± 1.5 h (overall mean ± SD). Strong linear correlations between the dose and Cmax and between the dose and the area under the curve were observed in both studies. Conclusion: Our results indicate that (deaminohydroxy)toremifene has pharmacokinetics suitable for single daily dosing. The prophylactic use of this agent in women susceptible to development of osteoporosis, cardiovascular disease and breast cancer could, therefore, be tested using a once-daily dosing schedule similar to those of other hormone-replacement therapy regimens. Springer-Verlag Berlin Heidelberg, 2000 Key words (Deaminohydroxy)toremifene nationallicence Pharmacokinetics nationallicence Triphenylethylene nationallicence FC-1271a nationallicence SERM nationallicence DeGregorio M. W. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut Wurz G. T. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut Taras T. L. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut Erkkola R. U. Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, FI aut Halonen K. H. Hormos Medical Ltd., Tykistökatu 6B, FIN-20520 Turku, Finland, FI aut Huupponen R. K. Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, FI aut https://doi.org/10.1007/s002280000176 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s002280000176 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- DeGregorio M. W. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut NATIONALLICENCE 700 1- Wurz G. T. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut NATIONALLICENCE 700 1- Taras T. L. Department of Internal Medicine, Division of Hematology/Oncology, Cancer Center, University of California, Davis, 4501 X Street Room 3016, Sacramento, California 95817, USA e-mail: mwdegregorio@ucdavis.edu Tel.: +1-916-7342360; Fax: +1-916-7342374, US aut NATIONALLICENCE 700 1- Erkkola R. U. Department of Obstetrics and Gynecology, Turku University Central Hospital, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, FI aut NATIONALLICENCE 700 1- Halonen K. H. Hormos Medical Ltd., Tykistökatu 6B, FIN-20520 Turku, Finland, FI aut NATIONALLICENCE 700 1- Huupponen R. K. Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland, FI aut Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer