Journal of steroid biochemistry最新文献_第10页

Metabolism of toremifene in the rat 托瑞米芬在大鼠体内的代谢

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90007-F

Hannu Sipilä, Lauri Kangas, Lauri Vuorilehto, Arm Kalapudas, Maire Eloranta, Marja Södervall, Reijo Toivola, Markku Anttila

{"title":"Metabolism of toremifene in the rat","authors":"Hannu Sipilä, Lauri Kangas, Lauri Vuorilehto, Arm Kalapudas, Maire Eloranta, Marja Södervall, Reijo Toivola, Markku Anttila","doi":"10.1016/0022-4731(90)90007-F","DOIUrl":"10.1016/0022-4731(90)90007-F","url":null,"abstract":"<div><p>Toremifene was labelled to a specific activity of about 20 μCi/mmol with tritium at positions 3 and 5 in the <em>para</em>-substituted phenyl ring. At these positions tritium is not eliminated within the metabolic pathways.</p><p>A mixture of unlabelled and labelled toremifene (5 or 10 mg/kg, 5 μCi/mg) was given i.v. or p.o. to Sprague-Dawley rats. The elimination of radioactivity was followed up by collecting urine and feces daily for 13 days. The elimination of toremifene which was similar after p.o. and i.v. administration took place mainly in the feces. About 70% of the total radioactivity was eliminated within 13 days, of this amount more than 90% in the feces. All applied radioactivity could be detected in three separate fractions according to the oxidative state of the side chain when counted by Berthold TLC Linear Analyzer. Each fraction was further separated into single metabolites by TLC or HPLC. Altogether 9 metabolites were identified and almost all methanol-extractable components were identified. The main metabolic pathways in the rat were 4-hydroxylation and <em>N</em>-demethylation. The side chain was further oxidized to alcohols and carboxylic acids. Small amounts of unchanged toremifene were found in the feces both after p.o. and i.v. administration indicating biliary secretion.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":"36 3","pages":"Pages 211-215"},"PeriodicalIF":0.0,"publicationDate":"1990-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90007-F","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13296446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 30

Effect of toremifene in breast cancer patients. Preliminary communication 托瑞米芬对乳腺癌患者的影响。初步的沟通

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90010-P

I. Hindy, É. Juhos, J. Szántó, I. Számel

引用次数: 11

Review of the pharmacological properties of toremifene 托雷米芬的药理学性质综述

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90003-B

Lauri Kangas

{"title":"Review of the pharmacological properties of toremifene","authors":"Lauri Kangas","doi":"10.1016/0022-4731(90)90003-B","DOIUrl":"10.1016/0022-4731(90)90003-B","url":null,"abstract":"<div><p>New compounds were synthesized with the aim to develop new anti-estrogenic antitumor drugs. The biological properties of the molecules were screened by (1) estrogen receptor (ER) binding, (2) effect on MCF-7 cells, (3) uterotrophic effect and inhibition of estradiol induced uterotropic effect and (4) antitumor effect in DMBA induced rat mammary cancer. One of the molecules, Fc-1157a = toremifene, exhibited the following characteristics: competitive inhibition of [<sup>3</sup>H]estradiol binding to ER (IC<sub>50</sub> = 0.3 μmol/l), inhibition of MCF-7 cell growth in a concentration-dependent manner and cell-killing effect at higher than 3 μmol/l concentrations. Minimal estrogenic dose of toremifene on rat uterus weight was about 40 times higher than that of tamoxifen. Toremifene had statistically significant effect against DMBA-induced rat mammary cancer. Further screening consisted of antitumor, pharmacokinetic and safety studies. Toremifene inhibited the growth of ER-negative, glucocorticoid sensitive, mouse uterine sarcoma in a dose-dependent manner. Pharmacokinetics and metabolism of toremifene resembled closely those of tamoxifen, but since the chlorine atom of the toremifene molecule was not metabolically cleaved tamoxifen and toremifene did not have chemically similar metabolites. Toremifene was well tolerated in animal toxicity studies. No hyperplastic or neoplastic nodules, which were seen in almost all high-dose (48 mg/kg for 24 weeks) tamoxifen-treated rats, were found in toremifene-treated rats (dose 48 mg/kg). In clinical phase I studies in healthy voluntary postmenopausal women, no side effects were reported, at doses ⩽ 460 mg, neither after a single dose nor after five daily doses. At the dose of 680 mg two out of five persons experienced vertigo and headache. Toremifene, at the dose of 68 mg daily, had antiestrogenic effect on estradiol-induccd human vaginal epithelial cells. Clinical phase II studies have confirmed that toremifene has a promising antitumor effect.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":"36 3","pages":"Pages 191-195"},"PeriodicalIF":0.0,"publicationDate":"1990-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90003-B","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13296442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 72

A phase II study of toremifene in carcinoma corporis uteri. Preliminary communication 托瑞米芬治疗子宫癌的II期研究。初步的沟通

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90017-M

G. Horváth, C. Tropé, H.-E. Almbo

引用次数: 1

Treatment of advanced breast cancer with 20 mg toremifene, a phase II study. Preliminary communication 20毫克托瑞米芬治疗晚期乳腺癌，一项II期研究。初步的沟通

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90011-G

S. Pyrhönen , R. Valavaara , M. Heikkinen , P. Rissanen , G. Blanco , E. Nordman , L.R. Holsti , A. Hajba

引用次数: 14

Safety and efficacy of toremifene in breast cancer patients. A phase II study 托瑞米芬在乳腺癌患者中的安全性和有效性。II期研究

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90012-H

R. Valavaara, S. Pyrhönen, M. Heikkinen, P. Rissanen, G. Blanco, E. Nordman, P. Taskinen, L.R. Holsti, A. Hajba

{"title":"Safety and efficacy of toremifene in breast cancer patients. A phase II study","authors":"R. Valavaara, S. Pyrhönen, M. Heikkinen, P. Rissanen, G. Blanco, E. Nordman, P. Taskinen, L.R. Holsti, A. Hajba","doi":"10.1016/0022-4731(90)90012-H","DOIUrl":"10.1016/0022-4731(90)90012-H","url":null,"abstract":"<div><p>46 postmenopausal women with estrogen receptor positive breast cancer entered a phase II study with a novel antiestrogen, toremifene. Patients had either recurrent or primarily inoperable advanced disease. No prior or concurrent cytostatic or hormonal treatment was allowed. Eight patients (17%) achieved complete response (CR), 17 (37%) partial response (PR) and 13 (28%) had stabilization or their disease at least for three months. The mean durations of responses were 52+, 53+ and 27+ weeks, respectively, with 5 patients in CR, 6 in PR and 1 with no change (NC) still continuing the treatment. No significant differences could be seen in response rates according to the concentration of estrogen receptors or presence of progesteron receptors in this group of patients. Toxicity was not a problem, in general, the treatment was well tolerated. Two side effects (sweating and vertigo) were classified as severe and one patient after achieving PR interrupted the treatment because of tremor.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":"36 3","pages":"Pages 229-231"},"PeriodicalIF":0.0,"publicationDate":"1990-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90012-H","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13296351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Pharmacokinetics of toremifene 托瑞米芬的药代动力学

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90019-O

M. Anttila, R. Valavaara , S. Kivinen , J. Mäenpää

引用次数: 57

Phase II clinical study of toremifene in patients with metastatic breast cancer. Preliminary communication 托瑞米芬治疗转移性乳腺癌的II期临床研究。初步的沟通

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90014-J

H. Modig , S. Borgström , I. Nilsson , G. Westman

引用次数: 21

In vitro and in vivo binding of toremifene and its metabolites in rat uterus 托瑞米芬及其代谢物在大鼠子宫内体外结合的研究

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90004-C

Niklas H. Simberg , James T. Murai , Pentti K. Siiteri

{"title":"In vitro and in vivo binding of toremifene and its metabolites in rat uterus","authors":"Niklas H. Simberg , James T. Murai , Pentti K. Siiteri","doi":"10.1016/0022-4731(90)90004-C","DOIUrl":"10.1016/0022-4731(90)90004-C","url":null,"abstract":"<div><p>The <em>in vitro</em> binding affinities of toremifene (TOR), 4-hydroxy toremifene (4-OH-TOR) and several other metabolites for the rat uterine cytosolic estrogen receptor were compared with those of tamoxifen (TAM) and 4-hydroxy tamoxifen (4-OH-TAM). Only small differences were observed and the binding affinities of both 4-hydroxy metabolites were similar to that of estradiol (E2). Uterine uptake and subcellular distribution of [<sup>3</sup>H]TOR and [<sup>3</sup>H]TAM were then compared at 1, 8 and 72 h after administration to castrated rats. The uptake and retention of both antiestrogens were similar at all times. In each case the amount of nuclear bound radioactivity declined to low levels at 8 and 72 h but the ratios of 4-OH-TAM/TAM and 4-OH-TOR/TOR determined by HPLC analysis increased dramatically at 72 h. The level of radioactivity in both plasma and uterine cytsol at 72 h was significantly higher following [<sup>3</sup>H]TAM administration. However, most of the radioactivity appeared to be in a conjugated form since it was not extractable with solvent. Finally, the ability of prior administration of each antiestrogen (100 mg/kg) to block uterine [<sup>3</sup>H]estradiol uptake was examined at 3 and 7 days. It was found that uterine wet weights were higher than control one week after administration of both compounds. Prior administration of TOR increased nuclear uptake of [<sup>3</sup>H]E2 whereas TAM had no effect. The results of these experiments suggest that toremifene and tamoxifen have very similar <em>in vitro</em> and <em>in vivo</em> binding properties but differences in metabolism exist that may be important.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":"36 3","pages":"Pages 197-202"},"PeriodicalIF":0.0,"publicationDate":"1990-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90004-C","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13296443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 12

Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: Phase I study 托瑞米芬不同剂量对健康绝经后志愿者临床化学、血液学和激素水平的影响:I期研究

Journal of steroid biochemistry Pub Date : 1990-06-22 DOI: 10.1016/0022-4731(90)90008-G

S. Kivinen , J. Mäenpää

{"title":"Effect of toremifene on clinical chemistry, hematology and hormone levels at different doses in healthy postmenopausal volunteers: Phase I study","authors":"S. Kivinen , J. Mäenpää","doi":"10.1016/0022-4731(90)90008-G","DOIUrl":"10.1016/0022-4731(90)90008-G","url":null,"abstract":"<div><p>Toremifene was given within the dose range of 3–680 mg as a single dose or on five consecutive days to 72 postmenopausal volunteers. Blood samples for clinical chemistry were taken hourly up to 7 h and 1, 2, 3, 7, 10 and 15 days after the last dose of toremifene. The concentrations of serum bilirubin, creatinine, amylase, free thyroxine, cortisol, prolactin, electrolytes and blood glucose remained unchanged at all dose levels. A statistically significant decrease was observed in liver enzymes (ASAT, ALAT, ALP) at the dose levels of 220–680 mg, whereas γ-GT remained unchanged. A decrease in the concentration of LH and FSH was observed at the dose levels of 46 mg or higher and 220 mg or higher, respectively. These hormonal changes including the increase of SHBG at the dose levels of 220–680 mg and the decrease of antithrombin III (220–680 mg) may be attributed to a weak estrogen-like effect of toremifene. Side effects were minimal: pulse rate, blood pressure and ECG remained unchanged during the test period. Only two patients on 680 mg dose suffered from nausea and vertigo, and one of them discontinued the medication.</p></div>","PeriodicalId":17138,"journal":{"name":"Journal of steroid biochemistry","volume":"36 3","pages":"Pages 217-220"},"PeriodicalIF":0.0,"publicationDate":"1990-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/0022-4731(90)90008-G","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"13296447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 26