Pharmacokinetics of Spironolactone After a Single Dose: Evaluation of the true Canrenone Serum Concentrations During 24 Hours

Merkus, F. W. H. M.; Overdiek, J. W. P. M.; Cilissen, J.; Zuidema, J.

doi:10.3109/10641968309048824

Cited by 16 publications

(4 citation statements)

References 12 publications

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“…In the dose range 1-10 mol/L, compatible with the concentrations reached by the drug in the serum after oral administration, [43][44][45][46] canrenone is able to inhibit cell growth and chemotaxis induced by PDGF without affecting basal cell proliferation and motility. To elucidate which step(s) of PDGF signaling are affected by canrenone, the effects of this drug on the downstream pathways induced by this growth factor were investigated.…”

Section: Discussionmentioning

confidence: 82%

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

et al. 2003

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Section: Discussionmentioning

confidence: 82%

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

et al. 2003

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“…This conclusion proved erroneous being based on non-specific fluorometric assay findings [12,13]. Assays of spironolactone and its metabolites by the use of high performance liquid chromatography (HPLC) have established that fluorometrically determined levels of canrenone overestimate true canrenone levels [14]. Using HPLC, the predominant metabolite, 7α-methylspironolactone (TMS) [15], was found to account for around 80% of the K + -sparing effect of spironolactone.…”

Section: Spironolactonementioning

confidence: 97%

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

2005

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Spironolacotone and eplerenone are mineralocorticoid-blocking agents used for their ability to block both the epithelial and non-epithelial actions of aldosterone. Spironolactone is a non-selective mineralocorticoid receptor antagonist with moderate affinity for both progesterone and androgen receptors. The latter property increases the likelihood of endocrine side effects with spironolactone including loss of libido, menstrual irregularities, gynecomastia and impotence. Eplerenone is a next generation aldosterone receptor antagonist selective for aldosterone receptors alone. This lesser affinity for progesterone and androgen receptors was arrived at by replacing the 17-alpha -thioacetyl group of spironolactone with a carbomethoxy group. Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites. Both eplerenone and spironolactone are effective antihypertensive agents and each has been shown to improve the morbidity and mortality of heart failure. Eplerenone or spironolactone use can increase serum potassium values and occasionally results in clinically relevant hyperkalemia. This is more apt to occur with spironolactone due to the very long half-life of several of its active metabolites.

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“…Using this methodology, it was demonstrated that canrenone plasma concentrations were 5 times higher after potassium canrenoate administration than the same dose of spironolactone ( Dahlöf et al 1979 ). In contrast to the high proportion of canrenone generation after potassium canrenoate application, the canrenone proportion of the metabolites generated after spironolactone administration contributes only to about 15% after a single dose ( Merkus et al 1983 ) and about 23% after multiple doses ( Gardiner et al 1989 ). These results demonstrate that spironolactone and potassium canrenoate are very different in their metabolism, especially because a number of important sulfur-containing metabolites, i.e.…”

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

confidence: 98%

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

Kolkhof

Bärfacker

2017

Journal of Endocrinology

196

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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Pharmacokinetics of Spironolactone After a Single Dose: Evaluation of the true Canrenone Serum Concentrations During 24 Hours

Cited by 16 publications

References 12 publications

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

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

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