Potassium Canrenoate

Potassium canrenoate is a competitive antagonist of aldosterone receptor [1].

Aldosterone is a steroid hormone and plays an important role in the regulation of blood pressure by increasing reabsorption of ions and water in the kidney.

In cultured rat and human cells, potassium canrenoate produced genotoxic effects in a doce-dependant way [2].

In male Wistar rats injected with isoprenaline (400 mg/kg), heart and left ventricular weights increased significantly. While potassium canrenoate (20 mg/kg/day) relieved this increase. Potassium canrenoate significantly reduced the fibrosis induced by isoprenaline [1]. In 30 essential hypertensives, canrenoate potassium reduced intraerythrocyte Na+ content and increased Na-K pump [3]. In 15 patients with idiopathic primary aldosteronism, potassium canrenoate normalized the aldosterone/plasma renin activity (PRA) ratio [4].

References:
[1].  Bos R, Mougenot N, Médiani O, et al. Potassium canrenoate, an aldosterone receptor antagonist, reduces isoprenaline-induced cardiac fibrosis in the rat. J Pharmacol Exp Ther, 2004, 309(3): 1160-1166.
[2].  Martelli A, Mattioli F, Carrozzino R, et al. Genotoxicity testing of potassium canrenoate in cultured rat and human cells. Mutagenesis, 1999, 14(5): 463-472.
[3].  Niutta E, Cusi D, Colombo R, et al. Antihypertensive effect of captopril, canrenoate potassium, and atenolol. Relations with red blood cell sodium transport and renin. Am J Hypertens, 1988, 1(4 Pt 1): 364-371.
[4].  Armanini D, Scaroni C, Mattarello MJ, et al. Idiopathic primary hyperaldosteronism: normalization of plasma aldosterone after one month withdrawal of long-term therapy with aldosterone-receptor antagonist potassium canrenoate. J Endocrinol Invest, 2005, 28(3): 236-240.

Potassium canrenoate treatment in paediatric patients: a population pharmacokinetic study using novel dried blood spot sampling.[Pubmed:23846862]

J Hypertens. 2013 Sep;31(9):1901-8.

OBJECTIVE: To characterize the population pharmacokinetics of canrenone following administration of Potassium Canrenoate (K-canrenoate) in paediatric patients. METHODS: Data were collected prospectively from 37 paediatric patients (median weight 2.9 kg, age range 2 days-0.85 years) who received intravenous K-canrenoate for management of retained fluids, for example in heart failure and chronic lung disease. Dried blood spot (DBS) samples (n=213) from these were analysed for canrenone content and the data subjected to pharmacokinetic analysis using nonlinear mixed-effects modelling. Another group of patients (n=16) who had 71 matching plasma and DBS samples was analysed separately to compare canrenone pharmacokinetic parameters obtained using the two different matrices. RESULTS: A one-compartment model best described the DBS data. Significant covariates were weight, postmenstrual age (PMA) and gestational age. The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) in DBS were CL/F (l/h) = 12.86 x (WT/70.0) x e [0.066 x (PMA - 40]) and V/F (l) = 603.30 x (WT/70) x (GA/40) where weight is in kilograms. The corresponding values of CL/F and V/F in a patient with a median weight of 2.9 kg are 1.11 l/h and 20.48 l, respectively. Estimated half-life of canrenone based on DBS concentrations was similar to that based on matched plasma concentrations (19.99 and 19.37 h, respectively, in 70 kg patient). CONCLUSION: The range of estimated CL/F in DBS for the study population was 0.12-9.62 l/h; hence, bodyweight-based dosage adjustment of K-canrenoate appears necessary. However, a dosing scheme that takes into consideration both weight and age (PMA/gestational age) of paediatric patients seems more appropriate.

Electrophysiological and antiarrhythmic properties of potassium canrenoate during myocardial ischemia-reperfusion.[Pubmed:25389106]

J Cardiovasc Pharmacol Ther. 2015 May;20(3):313-21.

INTRODUCTION: Recent clinical studies have reported the potential benefit of an early mineralocorticoid receptor (MR) blockade with Potassium Canrenoate (PC) on ventricular arrhythmias (VAs) occurrence in patients experiencing an ST-segment elevation myocardial infarction (STEMI). However, most of the electrophysiological properties of PC demonstrated to date have been investigated in normoxic conditions, and therefore, in vitro experiments during an acute myocardial ischemia-reperfusion were lacking. MATERIALS AND METHODS: We used rabbit in vitro models and standard microelectrode technique to assess the electrophysiological impact of PC during myocardial ischemia-reperfusion, including right ventricle mimicking the "border zone" existing between normal and ischemic/reperfused areas (1 micromol/L, 10 and 100 nmol/L), isolated right ventricle, and sinoatrial node (SAN) experiments (1 micromol/L, respectively). RESULTS: During ischemia-reperfusion, acute superfusion of PC 100 nmol/L prevented the increase in action potential (AP) duration at 90% of repolarization (APD90) dispersion between ischemic and nonischemic areas and in VAs occurrence induced by aldosterone 10 nmol/L (86 +/- 3 vs 114 +/- 4 milliseconds for aldosterone alone, P < .05). Potassium Canrenoate also induced conduction blocks and significantly decreased Vmax during simulated ischemia (from 25 +/- 5 to 12 +/- 4, 14 +/- 3, and 14 +/- 5 V/s, respectively, for PC 1 micromol/L, 100, and 10 nmol/L, P < .05). Potassium Canrenoate 1 micromol/L demonstrated cycle length (CL)-dependent effects on APD90 and on Vmax, and it also reduced SAN beating CL (from 446 +/- 28 to 529 +/- 24 millisecond, P < .05). CONCLUSION: Our experimental study highlights new evidence for an antiarrhythmic impact of PC during myocardial ischemia-reperfusion via multiple channels modulation. These results are in line with recent clinical trials suggesting that an early MR blockade in STEMI may be preventive of VAs.

Population pharmacokinetic model of canrenone after intravenous administration of potassium canrenoate to paediatric patients.[Pubmed:22376078]

Br J Clin Pharmacol. 2012 Nov;74(5):864-72.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Little is known about the pharmacokinetics of Potassium Canrenoate/canrenone in paediatric patients WHAT THIS STUDY ADDS: A population pharmacokinetic model has been developed to evaluate the pharmacokinetics of canrenone in paediatric patients who received Potassium Canrenoate as part of their therapy in the intensive care unit. AIMS To characterize the population pharmacokinetics of canrenone following administration of Potassium Canrenoate to paediatric patients. METHODS: Data were collected prospectively from 23 paediatric patients (2 days to 10 years of age; median weight 4 kg, range 2.16-28.0 kg) who received intravenous Potassium Canrenoate (K-canrenoate) as part of their intensive care therapy for removal of retained fluids, e.g. in pulmonary oedema due to chronic lung disease and for the management of congestive heart failure. Plasma samples were analyzed by HPLC for determination of canrenone (the major metabolite and pharmacologically active moiety) and the data subjected to pharmacokinetic analysis using NONMEM. RESULTS: A one compartment model best described the data. The only significant covariate was weight (WT). The final population models for canrenone clearance (CL/F) and volume of distribution (V/F) were CL/F (l h(-1) ) = 11.4 x (WT/70.0)(0.75) and V/F (l) = 374.2 x (WT/70) where WT is in kg. The values of CL/F and V/F in a 4 kg child would be 1.33 l h(-1) and 21.4 l, respectively, resulting in an elimination half-life of 11.2 h. CONCLUSIONS: The range of estimated CL/F in the study population was 0.67-7.38 l h(-1) . The data suggest that adjustment of K-canrenoate dosage according to body weight is appropriate in paediatric patients.

Clinically insignificant negative interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone in new dimension vista LOCI digoxin immunoassay.[Pubmed:22628228]

J Clin Lab Anal. 2012 May;26(3):143-7.

Spironolactone, a potassium-sparing diuretic metabolized to canrenone is often used with digoxin to treat various conditions including congestive heart failure. Potassium Canrenoate is a similar drug, which is also metabolized to canrenone. Due to reported both positive and negative interference of spironolactone, Potassium Canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of spironolactone, Potassium Canrenoate, or canrenone and apparent digoxin values were measured using Dimension Vista LOCI digoxin assay, we observed no detected value except when aliquots were supplemented with very high amounts of Potassium Canrenoate or canrenone. However, we observed that apparent digoxin concentrations were very low. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin), were further supplemented with various amounts of spironolactone, Potassium Canrenoate, or canrenone and serum digoxin concentrations were remeasured using the LOCIdigoxin assay, only statistically significant falsely lower digoxin values (negative interference) were observed in specimens containing very high amounts of canrenone or Potassium Canrenoate. However, such small bias may not have any clinical significance. We conclude that new Dimension Vista LOCI digoxin assay is virtually free from interferences of spironolactone, Potassium Canrenoate, and their common metabolite canrenone.