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At least 19 recordsLinked to original sources
PubMed1990

Reversible pharmacokinetic profiles of canrenoic acid and its biotransformed product. Canrenone in the rat.

Pharmacokinetic profiles of canrenoic acid (CRA) and canrenone (CR), the reversible metabolite of CRA, were studied in the rat after intraportal (pv) administration in comparison with those after intravenous (iv) administration using an interconversion model. In the clearances for the irreversible loss. CL20 of CR was larger than CL10 of CRA. Nevertheless, the real plasma clearance of CR was less than that of CRA. The distribution volume V1 of CRA was almost close to the real distribution volume Vss.real.D of CRA at the steady state. The hepatic available fraction of CRA, FH1 and sequential hepatic available fraction of generated metabolite, FH2, were estimated. Simultaneous computer multi-line fitting of plasma concentration-time data was carried out and the adequacy of pharmacokinetic parameters in this model was tested using the iterative nonlinear least-squares regression program, MULTI.

Animals↗
PubMed2005

Spironolactone and its main metabolite canrenoic acid block hKv1.5, Kv4.3 and Kv7.1 + minK channels.

Both spironolactone (SP) and its main metabolite, canrenoic acid (CA), prolong cardiac action potential duration and decrease the Kv11.1 (HERG) current. We examined the effects of SP and CA on cardiac hKv1.5, Kv4.3 and Kv7.1+minK channels that generate the human I(Kur), I(to1) and I(Ks), which contribute to the control of human cardiac action potential duration.hKv1.5 currents were recorded in stably transfected mouse fibroblasts and Kv4.3 and Kv7.1 + minK in transiently transfected Chinese hamster ovary cells using the whole-cell patch clamp. SP (1 microM) and CA (1 nM) inhibited hKv1.5 currents by 23.2 +/- 3.2 and 18.9 +/- 2.7%, respectively, shifted the midpoint of the activation curve to more negative potentials and delayed the time course of tail deactivation.SP (1 microM) and CA (1 nM) inhibited the total charge crossing the membrane through Kv4.3 channels at +50 mV by 27.1 +/- 6.4 and 27.4 +/- 5.7%, respectively, and accelerated the time course of current decay. CA, but not SP, shifted the inactivation curve to more hyperpolarised potentials (V(h)-37.0 +/- 1.8 vs -40.8 +/- 1.6 mV, n = 10, P < 0.05).SP (10 microM) and CA (1 nM) also inhibited Kv7.1 + minK currents by 38.6 +/- 2.3 and 22.1 +/- 1.4%, respectively, without modifying the voltage dependence of channel activation. SP, but not CA, slowed the time course of tail current decay.CA (1 nM) inhibited the I(Kur) (29.2 +/- 5.5%) and the I(to1) (16.1 +/- 3.9%) recorded in mouse ventricular myocytes and the I(K) (21.8 +/- 6.9%) recorded in guinea-pig ventricular myocytes.A mathematical model of human atrial action potentials demonstrated that K(+) blocking effects of CA resulted in a lengthening of action potential duration, both in normal and atrial fibrillation simulated conditions. The results demonstrated that both SP and CA directly block hKv1.5, Kv4.3 and Kv7.1 + minK channels, CA being more potent for these effects. Since peak free plasma concentrations of CA ranged between 3 and 16 nM, these results indicated that blockade of these human cardiac K(+) channels can be observed after administration of therapeutic doses of SP. Blockade of these cardiac K(+) currents, together with the antagonism of the aldosterone proarrhythmic effects produced by SP, might be highly desirable for the treatment of supraventricular arrhythmias.

Animals↗
PubMed2005

Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) "probes" for human udp-glucuronosyltransferases.

Relatively few selective substrate and inhibitor probes have been identified for human UDP-glucuronosyltransferases (UGTs). This work investigated the selectivity of trifluoperazine (TFP), as a substrate, and amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone, as inhibitors, for human UGTs. Selectivity was assessed using UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B7, and 2B15 expressed in HEK293 cells. TFP was confirmed as a highly selective substrate for UGT1A4. However, TFP bound extensively to both HEK293 lysate and human liver microsomes in a concentration-dependent manner (fuinc 0.20-0.59). When corrected for nonspecific binding, Km values for TFP glucuronidation were similar for both UGT1A4 (4.1 microM) and human liver microsomes (6.1+/-1.2 microM) as the enzyme sources. Of the compounds screened as inhibitors, hecogenin, alone, was selective; significant inhibition was observed only for UGT1A4 (IC50 1.5 microM). Using phenylbutazone and quinine as "models," inhibition kinetics were variously described by competitive and noncompetitive mechanisms. Inhibition of UGT2B7 by quinidine was also investigated further, because the effects of this compound on morphine pharmacokinetics (a known UGT2B7 substrate) have been ascribed to inhibition of P-glycoprotein. Quinidine inhibited human liver microsomal and recombinant UGT2B7, with respective Ki values of 335+/-128 microM and 186 microM. In conclusion, TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies. Amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone are nonselective UGT inhibitors.

Cell Line↗
PubMed2003

Spironolactone and its main metabolite, canrenoic acid, block human ether-a-go-go-related gene channels.

BACKGROUND: It has been demonstrated that spironolactone (SP) decreases the QT dispersion in chronic heart failure. In this study, the effects of SP and its metabolite, canrenoic acid (CA), on human ether-a-go-go-related gene (HERG) currents were analyzed. METHODS AND RESULTS: HERG currents elicited in stably transfected Chinese hamster ovary cells were measured with the whole-cell patch-clamp technique. SP decreased HERG currents in a concentration-dependent manner (IC50=23.0+/-1.5 micromol/L) and shifted the midpoint of the activation curve to more negative potentials (Vh=-13.1+/-3.4 versus -18.9+/-3.6 mV, P<0.05) without modifying the activation and deactivation kinetics. SP-induced block (1 micromol/L) appeared at the range of membrane potentials coinciding with that of channel activation, and thereafter, it remained constant, reaching 24.7+/-3.8% at +60 mV (n=6, P<0.05). CA (0.01 nmol/L to 500 micromol/L) blocked HERG channels in a voltage- and frequency-independent manner. CA at 1 nmol/L shifted the midpoint of the activation curve to -19.9+/-1.8 mV and accelerated the time course of channel activation (tau=1064+/-125 versus 820+/-93 ms, n=11, P<0.01). The envelope of the tail test demonstrated that at the very beginning of the pulses to +40 mV (25 ms), a certain amount of block was apparent (31.3+/-9.9%). CA did not modify the voltage-dependence of HERG channel inactivation (Vh=-60.8+/-5.6 versus -62.9+/-3.1 mV, n=6, P>0.05) or the kinetics of the reactivation process at any potential tested. CA and aldosterone also blocked the native I(Kr) in guinea-pig ventricular myocytes. CONCLUSIONS: At concentrations reached after administration of therapeutic doses of SP, CA blocked the HERG channels by binding to both the closed and open states of the channel.

Aldosterone↗
PubMed1991

Topical canrenoic acid. Quantification of the antiandrogenic activity in the hamster flank organ.

The topical antiandrogenic activity of potassium canrenoate (CAK), compared with that of spironolactone (SP), was assayed in vivo in female golden Syrian hamsters whose flank organs were stimulated by subcutaneous administration of testosterone propionate. Sebaceous glands and hair were measured by a computerized image analyzer. Pigmented spots, sebaceous gland areas, and the diameter of hairs of the treated flank organs were smaller in the groups that received CAK (1.6 mg/day) and SP (0.4 mg/day). The authors' results showed that CAK may act as a topical antiandrogen on the hamster flank organ when applied in concentrations four times greater than the minimal active dosage of SP. Potassium canrenoate may be a useful weak topical antiandrogen, and it could be used in androgen-related skin disorders involving both sebaceous glands and hair, especially in men. These concentrations could be verified by additional clinical investigations.

Administration, Topical↗
PubMed1985

Pharmacokinetics of spironolactone and potassium canrenoate in humans.

Plasma concentrations and urinary excretion of canrenone (III), canrenoic acid (IV) and canrenoic acid glucuronide (V) were determined by means of high performance liquid chromatography (HPLC) and fluorometry after oral administration of spironolactone (I) and potassium canrenoate (II) to human subjects. Comparison of both assays for III in plasma as well as in urine after administration of I showed marked differences. Plasma concentrations of III were significantly higher after administration of II than I, Cmax and AUC from II being 3--5 times larger than those from I by means of HPLC assay, while the fluorometrically determined values for III in plasma after administration of I and II did not differ as much from each other. On the other hand, in contrast to plasma, the amount of III excreted in urine after administration of I was much larger than that after II, i.e. 3--4 times greater by means of HPLC and over 10 times greater by means of fluorometry. These results strongly suggest that precursors of III are formed which have a higher renal clearance than that for III alone after oral administration of I. Considering the relative biological potency ratio of I and II, it is presumed that their pharmacological activities may relate to the urinary excretion of III. Plasma concentrations of IV were definitely higher after administration of II compared to those after I. Canrenoic acid (IV) was excreted mainly as glucuronide (V) in urine.

Adult↗
PubMed1977

Simultaneous automated determination of spironolactone metabolites in serum.

An automated two-phase method for the simultaneous fluorometric determination of the spironolactone metabolites canrenone (II) and canrenoic acid (III) in serum is described. The determination is performed by two dichloroethane extractions of the same serum sample at different pH values. The fluorescence developed in 65% (v/v) sulfuric acid is measured in two separate fluorometers (one each for canrenone and canrenoic acid). Comparable specificity and sensitivity to the manual procedure are obtained, with sensitivity limits of 20 ng of II/ml and of 30 ng of III/ml in serum. This method is applicable to the automated determination of drugs and metabolites in biological material when several extraction steps are involved.

Autoanalysis↗
PubMed2003

Prenatal morphine exposure suppresses mineralocorticoid receptor-dependent basal synaptic transmission and synaptic plasticity in the lateral perforant path in adult male rats.

The effects of prenatal morphine exposure (E11-18) on mineralocorticoid receptor (MR) modulation of synaptic plasticity were investigated in the lateral perforant path (LPP)-dentate gyrus granule cell synaptic system. Hippocampal slices were prepared from adult, prenatally saline- or morphine-exposed male rats. One hour prior to decapitation, some adult male rats were injected subcutaneously with saline or the MR antagonist, canrenoic acid (50 mg/kg). LPP was stimulated with high-frequency (2x100 Hz/0.5 s) and short-term plasticity (STP) and long-term potentiation (LTP) were evaluated at 5 and 30 min poststimulation, respectively. Prenatally saline-exposed male rats injected with saline 1 h prior to decapitation showed significantly higher levels of baseline, STP, and LTP than prenatally saline-exposed, canrenoic acid-treated males. In contrast, prenatally morphine-exposed male rats regardless of saline or canrenoic acid injection 1 h prior to decapitation were comparable in their baseline, STP, and LTP activities. Thus, the results demonstrate that canrenoic acid decreases the efficacy of the basal synaptic transmission in the LPP as well as suppresses synaptic plasticity in saline-exposed males. However, in adult morphine-exposed male rats, canrenoic acid has no other or further effects than a saline treatment suggesting that prenatal morphine exposure suppresses MR-dependent basal synaptic transmission as well as synaptic plasticity.

Animals↗
PubMed1991

Mechanism of ursodeoxycholic acid- and canrenoate-induced biliary bicarbonate secretion and the effect on glucose- and amino acid-induced cholestasis.

The mechanism of ursodeoxycholic acid (UDCA)- and canrenoate-induced bicarbonate choleresis was studied before and during the administration of glucose or amino acids in anaesthetized pigs. Previous studies have shown that the canalicular secretion has, on a molar basis, a relationship among the secretion of chloride, bicarbonate, and bile acids of 0.9, 0.3, and 1, respectively. Ductular secretion is associated with the transport of 0.25 mol chloride per 1 mol bicarbonate. In control experiments UDCA was associated with a biliary secretion of about 1.3 mol chloride and 0.5 mol bicarbonate per 1 mol bile acid, and canrenoate caused the secretion of 1.2 mol chloride per 1 mol bicarbonate. Intravenous infusion of glucose or amino acids increased these relationships, and after administration of UDCA or canrenoate, these relationships were still increased by at least 70% on average when compared with the control experiments. A reduction in bile secretion after glucose or amino acid infusion is opposed by UDCA or canrenoate. The effect of UDCA or canrenoate on bile secretion is not disturbed by glucose or amino acids. Both substances stimulate canalicular bicarbonate secretion and could be of importance in improving cholestatic conditions.

Amino Acids↗
PubMedDate not supplied

Identification of some human urinary metabolites of orally administered potassium canrenoate by stable isotope-labeling techniques.

A single oral dose (200 mg) of an equimolar mixture of potassium canrenoate and its 20,20,21,21-tetradeutero analogue was administered to three healthy men. The steroids in urine collected for 24 hr after dosage were isolated on XAD-2 resin, and purified and fractionated into groups by lipophilic gel chromatography before and after hydrolysis of conjugates. GC/MS analysis of these fractions allowed the detection and identification of canrenone, canrenoic acid and its ester glucuronide, 3 beta-hydroxy-3-deoxocanrenone, 3beta-hydroxy-4,5alpha-dihydro-3-deoxocanrenone and a 3epsilon-hydroxy-4,5,6,7-tetrahydro-3-deoxocanrenone. In addition a number of di- and trihydroxy compounds formed by reduction and hydroxylation were partially identified from their E1 and C1 mass spectra. The results provide information on the metabolism of oral potassium canrenoate in man, and demonstrate the utility of combining stable isotope labeling, lipophilic gel chromatography, and GC/MS in studies of steroidal spirolactones.

Administration, Oral↗
PubMed1985

In-vivo metabolites of spironolactone and potassium canrenoate: determination of potential anti-androgenic activity by a mouse kidney cytosol receptor assay.

We have established a sensitive and specific radioreceptor assay for androgen receptor active materials in plasma, using tritiated methyltrienolone ([3H]R1881) as tracer, and spayed mouse kidney cytosol receptor as the binding species. On radioreceptor assay, plasma from mice chronically administered spironolactone contained approximately 10 times higher levels of androgen receptor active material than from mice administered potassium canrenoate. In parallel bioassays (antagonism of the effect of testosterone on seminal vesicle weight), spironolactone was greater than 4 times as potent an antiandrogen as potassium canrenoate. Administered potassium canrenoate circulates as canrenoic acid, in equilibrium with its lactonized congener canrenone. Since over 80% of administered spironolactone is irreversibly converted to canrenone/canrenoic acid, its much higher anti-androgen activity on radioreceptor assay and bioassay may point to the generation of unidentified, minor metabolites with very high affinity for androgen receptors and/or a very long plasma half-life.

Animals↗
PubMed2000

Use of a three-factor interpretive optimisation strategy in the development of an isocratic chromatographic procedure for the screening of diuretics in urine samples using micellar mobile phases.

Screening of diuretics in urine is feasible through direct injection of the samples into the chromatographic system and isocratic reversed-phase liquid chromatography (RPLC) with micellar-organic mobile phases of sodium dodecyl sulfate (SDS) and 1-propanol. The surfactant coverage of the chromatographic column makes the addition of organic competing amines less necessary than in conventional aqueous-organic RPLC to achieve well-shaped peaks. Also, the range of elution strengths of micellar mobile phases required to elute mixtures of hydrophobic and hydrophilic diuretics is smaller. This allows the isocratic separation of the diuretics within adequate analysis times. An interpretive methodology is applied to optimise the resolution of a mixture of 15 diuretics of diverse polarity and acid-base behaviour (althiazide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenoic acid, chlorthalidone, ethacrynic acid, furosemide, piretanide, probenecid, torasemide, triamterene, trichloromethiazide and xipamide), using pH and concentrations of surfactant and organic modifier in the mobile phase as separation factors. Twelve diuretics were resolved in 25 min using 0.055 M SDS-6.0% 1-propanol at pH 3.0. The mixture of 15 diuretics was also resolved with two mobile phases showing complementary behaviour: 0.05 M SDS-5.6% 1-propanol at pH 5.4 and 0.11 M SDS-5.4% 1-propanol at pH 4.2. The results were applied to the analysis of urine samples with limits of detection similar to those usually reported for aqueous-organic RPLC, taking into account that the samples were injected without any previous treatment to separate or preconcentrate the analytes.

Calibration↗
PubMed2004

Effects of pH and the presence of micelles on the resolution of diuretics by reversed-phase liquid chromatography.

A comparative study on the performance of two RPLC modes on the separation of 18 diuretics with diverse acid-base behaviour (acetazolamide, althiazide, amiloride, bendroflumethiazide, benzthiazide, bumetanide, canrenoic acid, chlorothiazide, chlorthalidone, ethacrynic acid, furosemide, hydrochlorothiazide, piretanide, probenecid, spironolactone, triamterene, trichloromethiazide and xipamide) was carried out. A conventional octadecylsilane column and acidic acetonitrile-water mobile phases, in the absence and presence of micelles of the anionic surfactant sodium dodecyl sulphate (SDS), were used. The effects of pH and the modifiers acetonitrile and SDS on peak asymmetry, efficiency, selectivity, resolution and analysis time, were examined. The comparison of both RPLC modes (aqueous- and micellar-organics) was done using the same processing tools, applying several polynomial and mechanistic equations to describe the retention. The best separations were obtained by maximising the product of peak purities, considering a wide range of experimental conditions. The study illustrates that, despite the theoretical and practical complexity of the problem, the predicted optimal chromatograms can be reproduced experimentally with great accuracy. None of the examined RPLC modes was able to yield baseline separation of the 18 diuretics. However, their selectivity was complementary, being appropriate for different combinations of a smaller number of the assayed diuretics.

Chromatography, Liquid↗
PubMed2001

Determination and characterization of diuretics in human urine by liquid chromatography coupled to pneumatically assisted electrospray ionization mass spectrometry.

The aim of this work was to develop a method for the characterization and determination of diuretics in human urine samples by liquid chromatography (LC) coupled to pneumatically assisted electrospray ionization (ES) mass spectrometry (MS). The diuretics studied were substances forbidden by the IOC such as trichlormethiazide, furosemide, canrenoic acid, benzthiazide, bendroflumethiazide, bumetanide, etacrynic acid and spironolactone. For this purpose, the operational parameters of electrospray, such as counter electrode voltage, capillary voltage, sample cone voltage and source temperature, were optimized in order to obtain the best signal stability and the highest sensitivity for the greatest number of diuretic agents. The optimized separation method was successfully coupled with the MS system to analyze the above-mentioned diuretics extracted from spiked urine samples by a liquid extraction and clean-up procedure at basic pH, using ethyl acetate as solvent and the salting-out effect (NaCl). The mass spectra obtained provide adequate information for identification purposes. Positive urine samples obtained from athletes were also analyzed. The presence of these substances in human urine was confirmed by this method, making LC/ES-MS an analytical tool to be considered in the area of antidoping control.

Chromatography, Liquid↗
PubMed1984

Comparison of plasma levels of canrenone and metabolites after base hydrolysis in young and elderly subjects following single and multiple doses of spironolactone.

Plasma levels of canrenone and 'total metabolites' after base hydrolysis were compared in young and elderly subjects following single and multiple doses of spironolactone. After the initial dose on Day 1, plasma levels of canrenone and 'total metabolites' were higher in the young than in the elderly group, and significant differences were found between the two age groups in the AUC for both canrenone and 'total metabolites'. However, these differences between the two age groups diminished after multiple dosing on Day 8, and the steady state pre-dose plasma levels of canrenone and 'total metabolites' were significantly higher in the elderly subjects. The accumulation ratios of canrenone and 'total metabolites' were significantly higher in the elderly than in the young subjects. Both canrenone and canrenoic acid were extensively bound to plasma protein, but no differences were found between the two age groups in protein binding. Observed differences in plasma levels after single and multiple dosing between young and old subjects may be consequences of many factors such as a proportionate shift in metabolism with age; impaired oral absorption of the parent compound; and/or altered volume of distribution of the drug.

Adult↗
PubMedDate not supplied

[Relative bioavailability in man of 2 pharmaceutical forms of canrenone].

The relative bioavailability of 100 mg canrenone capsules and the commercial 50 mg capsules has been determined in 12 healthy male subjects. The study was conducted in a cross over design. After the absorption phase canrenone plasma concentrations followed a biexponential decay. The half lives of the three phases observed were respectively 40.7 +/- 21.7 min, 1.94 +/- 0.558 hr and 18.5 +/- 3.93 hr after administration of a 100 mg capsules; they were respectively 31.8 +/- 14 min, 1.64 +/- 0.513 hr and 16.1 +/- 3.09 hr after administration of two 50 mg capsules. These values were similar to those reported in man. Bioequivalence of the two forms tested was ascertained by a two way analysis of variance and by the Westlake symmetrical confidence interval (95%). Peak plasma levels, Cmax, time to reach the peak, tmax, and the rate constant of absorption showed great inter and intra individual variations. In vivo hydrolysis of canrenone into canrenoic acid and subsequent lactonization of the acid are pH-dependent and could give rise to these variations if occurring before absorption.

Adult↗
PubMed1983

Metabolism of spirolactones by the rat testis in vitro.

Spironolactone (SPIR) has been shown in numerous clinical studies to produce sexual disorders. We studied the metabolism of canrenone (CAN), the main metabolite of SPIR, and of the analogue 6,7-dihydrocanrenone (DHC) by the rat testis in vitro. The metabolites produced during a 4 h incubation period were isolated by HPLC and identified by nmr-, ms-, ir- and uv-spectrometry. SPIR was not metabolised in a detectable amount. CAN was converted to canrenoic acid, several hydroxylated (15 beta-, 16 alpha-, 19-, 2OR- and 21S-OH-CAN) and one reduced metabolite (3 alpha-OH-CAN). When DHC was incubated, an analogous pattern was detected. It is concluded that CAN and DHC serve as substrates for steroid metabolism in the rat testis.

Animals↗