Binding of Spirolactones to Human Plasma Proteins

Chien, Yie W.; Hofmann, Lothar; Lambert, Howard J.; Lin, Tao

doi:10.1002/jps.2600650919

Cited by 13 publications

(5 citation statements)

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“…In addition, it is known that non-specific binding to plasma protein increases with lipophilicity (23). In microscopic studies, Tra-Cy5.5(SQ) showed non-specific uptake for HER2 negative Balb/3T3 cells.…”

Section: Discussionmentioning

confidence: 99%

In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies

Ogawa

Regino

Choyke

et al. 2009

Molecular Cancer Therapeutics

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Imaging with labeled monoclonal antibodies may be useful in detecting, staging, and monitoring tumors. Despite their high affinity and specificity, a critical limitation of antibody imaging is the high background signal due to prolonged clearance from the blood, which reduces the tumor-tobackground ratio. To address this problem, we developed a molecular imaging probe consisting of multiple selfquenching fluorophores [Cy5.5 or Alexa Fluor 680 (Alexa680)] conjugated to a monoclonal antibody (trastuzumab) to synthesize Tra-Cy5.5(SQ) or Tra-Alexa680(SQ), respectively. This agent only becomes fluorescently ''active'' after cellular internalization but is quenched in the unbound state leading to high tumor-to-background ratios. The in vitro quenching capacity for both conjugates was f9-fold. In vivo imaging experiments were done in mice bearing both 3T3/HER-2 + and BALB/3T3/ZsGreen/HER-2

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Section: Discussionmentioning

confidence: 99%

In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies

Ogawa

Regino

Choyke

et al. 2009

Molecular Cancer Therapeutics

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“…-besides aldosterone -progesterone, testosterone, cortisone and hydrocortisone (see also Table 3). [8], b data from [19], c data from [4], d data from [16] Concentration The aldosterone antagonists spironolactone and canrenone, on the other hand, produced very different dwelltime histograms. As shown in Fig.…”

Section: Inhibition Kineticsmentioning

confidence: 97%

Micromolar concentrations of steroids and of aldosterone antagonists inhibit the outwardly rectifying chloride channel with different kinetics

Rabe

Frömter

2000

Pflügers Arch – Eur J Physiol

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We used the patch-clamp technique to analyse the open/close kinetics of single, outwardly rectifying, intermediate-conductance (ORIC) Cl- channels from cultured epithelial cells under control conditions and in presence of different inhibitors. As observed previously in excised inside/out patches under control conditions, the switching kinetics were characterized by one open-state time constant (tau0 is approximately 30 ms) and three closed-state time constants (tau(cl)is approximately = to 0.2 ms, tau(c2) is approximately = 2 ms and tau(c3) is approximately = 60 ms). Aldosterone, six further steroids and two aldosterone antagonists inhibited channel open probability (NPo) concentration dependently with the potency at 10 micromol/l increasing in the sequence: hydrocortisone, corticosterone, P-oestradiol, cortisone, aldosterone, testosterone, progesterone, canrenone, spironolactone. Although all substances decreased tau(o), neither the steroids nor the aldosterone antagonists affected tau(cl), tau(c2) or tau(c3) or induced additional transitions with additional time constants. Instead, the steroids increased the prevalence of tau(c2) in the dwell-time histograms and the aldosterone antagonists increased the prevalence of tau(c3), both in a concentration-dependent manner. These observations may be explained by a model in which one open state leads to one of three closed states with rate constants alpha, beta and gamma, and in which beta or gamma increase under the influence of steroids or aldosterone antagonists, respectively. Cytosol, which contains a Cl- channel inhibitor of unknown molecular structure, (Krick et al., Pflügers Arch 418:491, 1991) was also tested, but the results did not conform to the blocker mechanisms described above. This shows that there are even further modes of channel inhibition and argues against the cytosolic Cl- channel inhibitor being a steroid.

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“…However, eplerenone’s improved selectivity goes along with a relatively low in vitro affinity for MR, which is about 40-fold lower than spironolactone (Garthwaite & McMahon 2004, Hu et al 2005, Fagart et al 2010). In vivo , eplerenone compensates for this lower in vitro potency at MR with a higher fraction of bioavailable compound, whereas spironolactone is bound 94% to human plasma proteins (Chien et al 1976) and eplerenone’s bound fraction is only about 50% (Inspra Prescribing Information 2002). Eplerenone was investigated in clinical phase I studies in a head-to-head manner with spironolactone published in 1989 (de Gasparo  et al 1989).…”

Section: Steroidal Mras (The First 45 Years Of Mra Randd)mentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

Kolkhof

Bärfacker

2017

Journal of Endocrinology

202

165

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The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct. The salient example is eplerenone, first described in 1987, coincidentally with the cloning of MR cDNA. Its launch on the market in 2003 paralleled intensive drug discovery programs for a new generation of non-steroidal MRAs. Now, 30 years after the cDNA cloning of MR and 60 years of clinical use of steroidal MRAs, novel non-steroidal MRAs such as apararenone, esaxerenone and finerenone are in late-stage clinical trials in patients with heart failure, chronic kidney disease (CKD), hypertension and liver disease. Finerenone has already been studied in over 2000 patients with heart failure plus chronic kidney disease and/or diabetes, and in patients with diabetic kidney disease, in five phase II clinical trials. Here, we reflect on the history of the various generations of MRAs and review characteristics of the most important steroidal and non-steroidal MRAs.

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Binding of Spirolactones to Human Plasma Proteins

Cited by 13 publications

References 1 publication

In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies

In vivo target-specific activatable near-infrared optical labeling of humanized monoclonal antibodies

Micromolar concentrations of steroids and of aldosterone antagonists inhibit the outwardly rectifying chloride channel with different kinetics

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor antagonists: 60 years of research and development

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