Disposition of bazedoxifene in rats

Chandrasekaran, Appavu; Ahmad, Samia; Shen, Li; DeMaio, William; Hultin, T A; Scatina, JoAnn

doi:10.3109/00498254.2010.492879

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…Both BZA and E 2 were dissolved in dimethyl sulphoxide (1 mg mL ‐1 stock). These protocols give plasma concentrations of 20.7 ± 2.1 ng mL ‐1 for BZA and 45.6 ± 7.8 pg mL ‐1 for E 2 , which closely fit those reported in other studies for both BZA and E 2 …”

Section: Methodssupporting

confidence: 88%

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Burguete

Jover‐Mengual

López‐Morales

et al. 2019

J Neuroendocrinology

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Because neuroprotection in stroke should be revisited in the era of recanalisation, the present study analysed the potential neuroprotective effect of the selective oestrogen receptor modulator, bazedoxifene acetate (BZA), in an animal model of diabetic ischaemic stroke that mimics thrombectomy combined with adjuvant administration of a putative neuroprotectant. Four weeks after induction of diabetes (40 mg kg -1 streptozotocin, i.p.), male Wistar rats were subjected to transient middle cerebral artery occlusion (intraluminal thread technique, 60 minutes) and assigned to one of three groups treated with either: vehicle, BZA (3 mg kg -1 day -1 , i.p.) or 17β-oestradiol (E 2 ) (100 μg kg -1 day -1 , i.p.). At 24 hours post-ischaemia-reperfusion, brain damage (neurofunctional score, infarct size and apoptosis), expression of oestrogen receptors (ER)α, ERβ and G protein-coupled oestrogen receptor), and activity of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK)1/2 and phosphoinositide 3-kinase/Akt pathways were analysed. At 24 hours after the ischaemic insult, both BZA-and E 2 -treated animals showed lower brain damage in terms of improved neurofunctional condition, decreased infarct size and decreased apoptotic cell death.Ischaemia-reperfusion induced a significant decrease in ERα and ERβ expression without affecting that of G protein-coupled oestrogen receptor, whereas BZA and E 2 reversed such a decrease. The ischaemic insult up-regulated the activity of both the MAPK/ERK1/2 and phosphoinositide 3-kinase/Akt pathways; BZA and E 2 attenuated the increased activity of the ERK1/2 pathway, without affecting that of the Akt pathway. The results of the present study lend further support to the consideration of BZA as an effective and safer alternative overcoming the drawbacks of E 2 with respect to improving diabetic ischaemic stroke outcome after successful reperfusion. K E Y W O R D S 17β-oestradiol, apoptosis, bazedoxifene, diabetes, ischaemic stroke, selective oestrogen receptor modulators How to cite this article: Burguete MC, Jover-Mengual T, López-Morales MA, et al. The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β-oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway. J Neuroendocrinol. 2019;31:e12751.

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Section: Methodssupporting

confidence: 88%

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Burguete

Jover‐Mengual

López‐Morales

et al. 2019

J Neuroendocrinology

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“…For this analysis, animal lung concentration data were available for anidulafungin (rat), bazedoxifene (rat), chloroquine (3 albino rat studies), favipiravir (monkey), hydroxychloroquine (2 albino rat studies), nitazoxanide (mouse), tamoxifen (rat), cyclosporine (rat), ritonavir (rat), azithromycin (mouse), dolutegravir (mouse), gilteritinib (albino rat), and lopinavir (rat). [23][24][25][26][27][28][29][30][31][32] Agreement between the predicted and measured K p was assessed by simple linear regression and by constructing Bland-Altman plots, the limits of agreement (mean ± 2 SD) were included in these plots as previously described. 33…”

Section: Data Analysis and Interpretationmentioning

confidence: 99%

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

Arshad

Pertinez

Box

et al. 2020

Clin Pharma and Therapeutics

139

148

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There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90) values recalculated from in vitro anti‐SARS‐CoV‐2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax) at an approved dose in humans (Cmax/EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax/EC90 ratio above 1. A more in‐depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir‐boosted), and sulfadoxine achieved plasma concentrations above their reported anti‐SARS‐CoV‐2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (KpUlung) was also simulated to derive a lung Cmax/half‐maximal effective concentration (EC50) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir‐boosted), tipranavir (ritonavir‐boosted), ivermectin, azithromycin, and lopinavir (ritonavir‐boosted) were all predicted to achieve lung concentrations over 10‐fold higher than their reported EC50. Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8‐fold and 1.5‐fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.

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“…1 A ). Studies in rats have shown that the half-lives of these SERMs are 13.5 h for Ral ( 11 ), 9.4 h for Las ( 41 ), and 3.8 h for Bza ( 10 ). The substances were given once/day, 5 days/wk, for 3 wk.…”

Section: Methodsmentioning

confidence: 99%

SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice

Börjesson

Farman

Movérare‐Skrtic

et al. 2016

American Journal of Physiology-Endocrinology and Metabolism

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The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)α, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ERαAF-1 for the estradiol (E2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ERαAF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ERαAF-1 (ERαAF-10) with E2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ERαAF-10 mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ERαAF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.

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Disposition of bazedoxifene in rats

Cited by 8 publications

References 18 publications

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

The selective oestrogen receptor modulator, bazedoxifene, mimics the neuroprotective effect of 17β‐oestradiol in diabetic ischaemic stroke by modulating oestrogen receptor expression and the MAPK/ERK1/2 signalling pathway

Prioritization of Anti‐SARS‐Cov‐2 Drug Repurposing Opportunities Based on Plasma and Target Site Concentrations Derived from their Established Human Pharmacokinetics

SERMs have substance-specific effects on bone, and these effects are mediated via ERαAF-1 in female mice

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