Endoxifen, a New Cornerstone of Breast Cancer Therapy: Demonstration of Safety, Tolerability, and Systemic Bioavailability in Healthy Human Subjects

Ahmad, Ateeq; Shahabuddin, Syed; Sheikh, Saifuddin; Kale, Prashant; Krishnappa, Manjunath; Rane, R C; Ahmad, Imran

doi:10.1038/clpt.2010.196

Cited by 74 publications

(52 citation statements)

References 20 publications

(38 reference statements)

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“…These high tissue concentrations are consistent with the large apparent distribution volume for tamoxifen, the parent drug, which is about 50-60 liters/kg in humans [24], indicating that most of the drug (99.9%) is present in peripheral compartments, and suggesting extensive tissue binding. This wide tissue distribution [23] and the relatively long apparent half-lives of NDMT and endoxifen (*14 and 44 days respectively) [25][26][27] in humans treated with tamoxifen are consistent with an extended period of tissue exposure. Sustained aromatase inhibition in vivo by these metabolites would therefore seem a possibility.…”

Section: Discussionsupporting

confidence: 62%

Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer

Desta

Flockhart

2011

Breast Cancer Res Treat

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The mechanism of tamoxifen action in the treatment of breast cancer is believed to be via active metabolites that act as potent estrogen receptor antagonists. Attempts to identify relationships between active metabolite concentrations and clinical outcomes have produced mixed results. Since anti-estrogenic effects may be brought about not only by estrogen antagonism, but also by reduced estrogen synthesis, we tested the ability of tamoxifen and its principal metabolites to inhibit aromatase in vitro. The activity of human aromatase in both recombinant and placental microsomal preparations was measured using the rate of generation of a fluorescent metabolite in the presence and absence of multiple concentrations of tamoxifen, endoxifen, N-desmethyl-tamoxifen, and Z-4-hydroxy-tamoxifen. Aromatase inhibition was further characterized by measuring the inhibition of testosterone metabolism to estradiol. The biochemical mechanisms of inhibition were documented and their inhibitory potency was compared. Using recombinant human aromatase, endoxifen, and N-desmethyl-tamoxifen were able to inhibit aromatase activity with K (i) values of 4.0 and 15.9 μM, respectively. Detailed characterization of inhibition by endoxifen and N-desmethyl-tamoxifen indicated non-competitive kinetics for both inhibitors. Similarly, endoxifen-inhibited testosterone metabolism via a non-competitive mechanism. No appreciable inhibition by tamoxifen or Z-4-hydroxy-tamoxifen was observed at similar concentrations. The relative inhibitory potency was: endoxifen > N-desmethyl-tamoxifen >>> Z-4-hydroxy-tamoxifen > tamoxifen. Similar data were obtained in human placental microsomes. Endoxifen and N-desmethyl-tamoxifen were found to be potent inhibitors of aromatase. Inhibition by these tamoxifen metabolites may contribute to the variability in clinical effects of tamoxifen in patients with breast cancer. Relationships between tamoxifen metabolite concentrations and clinical outcomes may be complex, and the biologic mechanisms that underlie these relationships may include aromatase inhibition.

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Section: Discussionsupporting

confidence: 62%

Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer

Desta

Flockhart

2011

Breast Cancer Res Treat

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“…Phase I studies were conducted to demonstrate the safety and tolerability of orally administered endoxifen in human subjects. The pharmacokinetic parameters showed plasma concentrations of endoxifen similar to that of CYP2D6 extensive metabolizers on tamoxifen can be achieved by 4 mg/day oral dose of endoxifen [30]. No significant or serious adverse effects were observed at the dose used in the study.…”

Section: Discussionmentioning

confidence: 81%

Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Damodaran

Pradhan

Umamaheswaran

et al. 2012

Cancer Chemother Pharmacol

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“…TMX is a prodrug with little affinity towards estrogen receptor, but its metabolites have high affinity and compete with estrogen for binding [70]. TMX also displays PKC inhibitory activity [71] and is the only PKC inhibitor that crosses the blood brain barrier [72].…”

Section: Pkc Translocation and Activitymentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

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Endoxifen, a New Cornerstone of Breast Cancer Therapy: Demonstration of Safety, Tolerability, and Systemic Bioavailability in Healthy Human Subjects

Cited by 74 publications

References 20 publications

Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer

Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer

Genetic polymorphisms of CYP2D6 increase the risk for recurrence of breast cancer in patients receiving tamoxifen as an adjuvant therapy

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

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