New data on Toremifene

[Swifto]

Expert Opin Drug Metab Toxicol. 2012 Apr;8(4):505-13. Epub 2012 Feb 23.

Pharmacokinetic evaluation of toremifene and its clinical implications for the treatment of osteoporosis.

Gennari L, Merlotti D, Stolakis K, Nuti R.

Source

University of Siena, Department of Internal Medicine, Endocrine-Metabolic Sciences and Biochemistry , Policlinico Le Scotte 53100-Siena , Italy +390577585364 ; +390577233446 ; [email protected].
Abstract

Introduction: Toremifene is a triphenylethylene selective estrogen receptor modulator (SERM) that differs from tamoxifen in a single chloride ion addition on a side chain, resulting in a potentially more favorable toxicity profile. Areas covered: This article reviews the pharmacokinetics of toremifene and its potential use for the treatment of osteoporosis. This article was based on articles found through a literature search containing the terms 'toremifene' and 'SERMs.' Expert opinion: Toremifene can be administered orally with an excellent bioavailability. The overall pharmacokinetic profile is remarkably similar to tamoxifen. Toremifene is highly metabolized in the liver and is eliminated primarily in the feces following enterohepatic circulation. Some of its metabolites retain biological activity. This SERM was approved by the FDA for the treatment of estrogen receptor-positive metastatic breast cancer and is under investigation for its potential skeletal benefits in men on androgen deprivation therapy. Despite the positive preclinical and clinical evidences for the prevention of bone loss and fractures, the chemopreventive effect on prostate cancer remains to be confirmed and an increased risk of venous thromboembolism was evidenced in a large Phase III trial. Thus, additional data are required to establish the full clinical profile of this compound and its potential advantages over antiresorptive agents commonly in use for the treatment of osteoporosis.

PMID:
22356442
[PubMed - in process]



Very similar to Tamoxifen, but less toxicity (we knew this). Not a whole lot of data on prostate cancer and thromboembolism is still evident.

I'm starting to think that in a lot more circumstances, Tore should be the SERM of choice. Its also widely available now and not too expensive.

Does anyone have access to the full paper? If so, please post a link or upload it...

[Swifto]

Drug Metab Dispos. 2012 Mar 20.

[Epub ahead of print]

Sulfation of 4-OH Toremifene: Individual Variability, Isoform Specificity, and Contribution to Toremifene Pharmacogenomics.

Koroth Edavana V, Dhakal IB, Yu X, Williams S, Kadlubar S.

Source

University of Arkansas for Medical Sciences.
Abstract

Toremifene (TOR) is a selective estrogen receptor modulator (SERM) used in adjuvant therapy for breast cancer, and more recently, in clinical trials for prostate cancer prevention. The chemical structure of TOR differs from tamoxifen (TAM) by the presence of a chlorine atom in the ethyl side chain, resulting in a more favorable toxicity spectrum with TOR. Additionally, some patients who fail on TAM therapy benefit from high-dose TOR therapy. Several studies have indicated that functional genetic variants in the TAM metabolic pathway influence response to therapy, but pharmacogenomic studies of patients treated with TOR are lacking. In this study, we examined individual variability in sulfation of 4-OH TOR (the active metabolite of TOR) in human liver cytosols from 104 subjects, and found approximately 30-fold variation in activity. 4-OH TOR sulfation was significantly correlated (r=0.98, P<0.0001) with β-naphthol sulfation (diagnostic for SULT1A1) but not with 17β estradiol sulfation, a diagnostic substrate for SULT1E1(r= 0.09, P=0.34). Examination of recombinant sulfotransferases revealed that SULT1A1 and SULT1E1 catalyzed 4-OH TOR sulfation, with apparent K(m)s of 2.6 μM and 6.4 μM and V(max)s of 8.5 and 5.5 nmol/min/mg proteins, respectively. 4-OH TOR sulfation was inhibited by 2, 6-dichloro-4-nitrophenol (IC(50) = 2.34 ± 0.19 μM), a specific inhibitor of SULT1A1. There was also a significant association between SULT1A1 genotypes and copy number and 4-OH TOR sulfation in human liver cytosols. These results indicate that variability in sulfation could contribute to response to TOR in the treatment of breast and prostate cancer.

PMID:
22434874
[PubMed - as supplied by publisher]

[Swifto]

Steroids. 2011 Nov;76(12):1400-6. Epub 2011 Jun 30.

Relevance of the selective oestrogen receptor modulators tamoxifen, toremifene and clomiphene in doping field: endogenous steroids urinary profile after multiple oral doses.

Mazzarino M, Braganò MC, de la Torre X, Molaioni F, Botrè F.

Source

Laboratorio Antidoping, Federazione Medico Sportiva Italiana, Largo Giulio Onesti, 1, 00197 Rome, Italy.
Abstract

The present study was performed to investigate the influence of the intake of selective oestrogen receptor modulators on the urinary endogenous steroids profile. For this purpose the circadian variability of luteinizing hormone, follicle-stimulating hormone, testosterone, 5α-androstan-3α,17β-diol, 5β-androstan-3α,17β-diol, epitestosterone, 4-androstenedione, androsterone and etiocholanolone were measured on eight subjects (four males and four females) by gas chromatography-mass spectrometry and chemiluminescent immunometric assay techniques before and after oral administration of multiple doses of either tamoxifen (80 mg for 2 days) or toremifene (120 mg for 2 days) or clomiphene (100 mg for 2 days). The individual baseline variability of the steroids studied was set up by collecting the urine samples every 3 h, for 3 days prior to the treatment; whereas the evaluation of the effects of the oral administration of multiple doses of selective oestrogen receptor modulators on the steroid urinary profile was assessed by collecting urine samples every three hours for at least five days from the first administration. The results of our measurements showed that, only in male subjects, the relative urinary concentrations of testosterone, epitestosterone and 4-androstenedione were significantly altered generally after the second day of drug administration. While no significant effects were recorded in both sexes on the luteinizing hormone, follicle-stimulating hormone, androsterone, etiocholanolone, 5α-androstan-3α,17β-diol and 5β-androstan-3α,17β-diol urinary levels and on testosterone/epitestosterone, 5α-androstan-3α,17β-diol/5β-androstan-3α,17β-diol and androsterone/etiocholanolone ratios.

Copyright © 2011 Elsevier Inc. All rights reserved.

Full paper on this would be excellent, tested LH and FSH after large initial dosing (I'm thinking PCT)... Even though these were in healthy eugondal subjects.

[Swifto]

So what enzymes does Toremifene inhibit?



Xenobiotica. 2011 Oct;41(10):851-62. Epub 2011 Jul 5.

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms.

Kim J, Peraire C, Solà J, Johanning KM, Dalton JT, Veverka KA.

Source

GTx, Inc., Memphis, TN, USA.
Abstract

Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.

[Swifto]

Favourable effects on lipids wit Toremifene when compared to Arimidex....

Also note 1mg Arimdiex for 6 months, "These lipid levels were not changed in those who received ANA.".



Effects of toremifene and anastrozole on serum lipids and bone metabolism in postmenopausal females with estrogen receptor-positive breast cancer: the results of a 2-year multicenter open randomized study.

Anan K, Mitsuyama S, Yanagita Y, Kimura M, Doihara H, Komaki K, Kusama M, Ikeda T.


Source

Department of Surgery, Kitakyushu Municipal Medical Center, Fukuoka, Japan. [email protected]
Abstract

The potential long-term adverse effects on quality of life have to be considered when selecting agents for adjuvant hormonal treatment for postmenopausal patients with estrogen receptor-positive breast cancer. We performed a 2-year multicenter randomized study to assess the differences in the time course effects between toremifene (TOR) and anastrozole (ANA) on serum lipid profiles and bone metabolism. This study assessed the serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-1 (Apo A1), and apolipoprotein B (Apo B) as lipid profiles and bone-specific alkaline phosphatase (BAP) and the N-telopeptide of type-I collagen (NTX) as bone turnover markers in patients who received daily doses of 40 mg and 1 mg for TOR and ANA, respectively. A decreased serum level of TC, LDL-C, and Apo B was, respectively, observed at 6 months in 6.2, 12.9, and 13.8% of the patients who received TOR compared with the baseline. These decreases were maintained for at least 24 months. These lipid levels were not changed in those who received ANA. In the TOR patients, there was an increase in the serum level of HDL-C and Apo A1 at 6 months in 17.1 and 16.3%, respectively, which was maintained for at least 24 months, whereas these levels were almost stable in the patients who received ANA. Serum BAP decreased by 12.1% at 12 months and further decreased at 24 months and the serum NTX decreased by 22.0% at 6 months, which was maintained for at least 24 months in the patients who received TOR. In contrast, the serum BAP was increased by 26.0% at 6 months and by 29.2% at 12 months and the serum NTX increased by 21.3% at 24 months compared with baseline in those received ANA. However, the serum BAP increase was not significant at 24 months. TOR provides better effects than ANA in terms of lipid profiles and bone metabolism in postmenopausal females with early breast cancer.

PMID:
21638048
[PubMed - in process]

[crakawoody]

Can you sum this up in dumbarse language so I can understand?

[ironbeck]

Wow that is some impressive data and input.....tks man, even though its long winded its importance is of so value.