Plasma and urinary levels of triamterene and certain metabolites after oral administration to man

Summary The plasma and urinary levels of triamterene and two metabolites were measured using a specific method of analysis. Urinary excretion was completed after 48 h, which permitted a rough estimate of its half-life as longer than two hours. The areas under the curve were 672.5±160.3 and 1.311.3±399.1 µg/ml × h after the triameterene 150 mg and 300 mg p.o., respectively and correspondingly 4.2±1.4% and 3.7±0.6% of the dose were excreted as unchanged drug. The principal metabolite of triamterene found was the sulfate conjugate. The area under the curve of this metabolite amounted to 6.672±2.120 and 11.941±5.005 µg/ml × h after the of 150 mg and 300 mg triamterene doses, respectively. The urinary excretion of the metabolite varied between 25.0±4.0% and 17.5±3.5% of the dose after either dose. In healthy subjects an effect on sodium excretion was observed after a dose of 150 mg, whereas the potassium-retaining effect was observed only after the dose of 300 mg.     

Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults

Summary The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F+T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men.A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC₄₈₀) F 2.58 g · h · ml^–1; F+T 2.46 g · h · ml^–1; FT 1.97 g · h · ml^–1. There was a significant reduction in the AUC₄₈₀ of plasma triameterene (F+T 204.9 g · h · l^–1; FT 130.2 g · h · l^–1). Sodium excretion after F+T and FT was more pronounced than after F (F+T 302 mmol; FT 311 mmol; F 259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F+T as well as after FT (F 121 mmol; F+T 104 mmol; FT 107 mmol).It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.     

Pharmacodynamics and pharmacokinetics of the basic triamterene analogue dimethylaminohydroxypropoxytriamterene

The diuretic, natriuretic and potassium retaining effects of dimethylaminohydroxypropoxytriamterene (RPH 2823), a basic triamterene derivative, were studied in male Wistar rats. Compared to triamterene (TA) RPH 2823 has a pronounced effect on urine volume and on the excretion of sodium; in addition it possesses a higher antikaliuretic potency than TA. In combination with furosemide, 2.5 mumol/kg RPH 2823 can avoid the kaliuresis of 25 mumol/kg furosemide. The pharmacokinetics of RPH 2823 after i.v. application of 1 mg/kg and 5 mg/kg were studied in female rats. The substance is not metabolized. RPH 2823 has a terminal elimination half-life of 3 h. About 47% of the given dose are excreted unchanged with urine. Furthermore, the volume of distribution VD beta and the total body clearance were calculated.     

Bioavailability and elimination kinetics of the combination furosemide-retard/triamterene

In a pharmacokinetic study on 18 healthy male volunteers the bioavailability and elimination kinetics of furosemide-retard and the combination furosemide-retard/triamterene were investigated and compared with the non-retarded form and another retard form of furosemide. The relative bioavailability of the non-retarded form of furosemide was distinctly reduced by the retardation in the substances investigated. It varied between 42-66% in the plasma and between 37-73% in the urine. In the combination with triamterene the serum concentration time curve of furosemide was only slightly modified but the renal excretion of furosemide was more influenced (36% for furosemide-retard and 25% for furosemide-retard/triamterene). In comparison, the values for the renal excretion of triamterene and OH-TA sulfate were distinctly greater than those obtained after administration of triamterene alone. A renewed increase of the plasma concentration and renal excretion of furosemide were observed between 9 and 10.5 h after administration of furosemide-retard/triamterene. This observation suggests that a further absorption of furosemide occurs as a consequence of the delayed release from distal parts of the small intestine or from the large intestine.     

Pharmacokinetics and biotransformation of benzbromarone in man

Summary After administration of a single oral dose of benzbromarone 100 mg to 7 subjects, the maximum serum level was 1.84±0.87 mg/l, and the elimination halflife was 2.77±1.07 h. The major metabolite, benzarone, could be detected in serum 3 h after administration of benzbromarone, and the maximum serum benzarone level of 0.79±0.21 mg/l occurred after 6 h. Benzarone had an elimination half-life from serum of 13.52±2.18 h. Both substances were excreted mainly via the liver and bile. In urine only benzarone -glucuronide could be detected; it amounted to 1.55% of the benzbromarone dose.     

Attenuation of the kaluretic properties of furosemide by triamterene (Dyrenium) in healthy volunteers

OBJECTIVE: To examine if concomitant administration of furosemide, a loop diuretic, with the potassium- and magnesium-sparing diuretic triamterene would decrease loss of potassium and magnesium while improving diuresis. METHODS: In this open-label, three-way crossover study, healthy subjects were randomized to receive treatment with 40 mg furosemide, with 150 mg triamterene, or treatment with 40 mg furosemide and 150 mg triamterene. Urine samples were collected 24 hours before dosing and between 0 - 1, 1 - 2, 2 - 3, 3 - 4, 4 - 6, 6 - 8, 8 - 12, and 12 - 24 hours post-dosing. Sodium and potassium levels were measured by an ion-selective electrode method. Magnesium was measured colorimetrically using a xylidyl blue reaction. RESULTS: Co-administration of furosemide with triamterene resulted in enhanced diuresis, particularly in the first 0 - 12 hours post-dose, compared with either furosemide or triamterene alone. Compared to individual treatments, combination therapy significantly increased urinary sodium excretion (p = 0.0001) while significantly decreasing urinary potassium excretion (p = 0.0001); importantly, the magnesium-sparing characteristic of triamterene was retained with furosemide co-administration. CONCLUSION: Triamterene, when used in combination with the loop diuretic, furosemide, preserves intracellular potassium and magnesium while enhancing the natriuretic effect of furosemide.     

Pharmacokinetics of furosemide in patients with hepatic cirrhosis

Summary The pharmacokinetics of furosemide was studied in 7 patients with diagnosed liver cirrhosis and in 7 healthy subjects. Furosemide in plasma and ascitic fluid was analyzed spectrofluorometrically. After a single intravenous dose, the cirrhotic patients showed lower initial plasma concentrations of furosemide because of the larger volume of distribution. The mean half-life in cirrhotic patients was significantly greater than in healthy volunteers. The longer half-life was associated with a reduction in the serum clearance of furosemide. Ascitic fluid volume in the patients ranged from 4.6 to 7.71. There was no significant amount of furosemide in the fluid. The diuretic interchange between this fluid and plasma was slow, as peak concentrations ranged from 0.3 to 0.5 µg/ml within 3 to 5 h after bolus administration of furosemide. Diuresis and urinary sodium excretion, 5 h after furosemide injection, were similar in both groups; larger potassium excretion was found in the cirrhotic patients.     

Comparison of the effects of muzolimine and furosemide in patients with end-stage renal failure on chronic dialysis

Summary The pharmacodynamic effects of muzolimine and furosemide were compared in a single dose cross-over study in 8 patients on regular dialysis treatment, who had a residual diuresis of more than 300 ml/day. The study periods comprised two dialysis-free intervals of 3 days. On the second dialysis-free day either muzolimine 240 mg or furosemide 240 mg was administered orally. Urine was collected in 12-h periods on the pre-treatment, treatment and post-treatment days, and the excretion of sodium, potassium, urea and creatinine were measured. After administration of muzolimine 240 mg urine volume rose to twice that of the previous day, and sodium excretion increased approximately threefold. In contrast, the effect of furosemide 240 mg was not as pronounced; the diuresis was only 1.6 times that on the previous day and natriuresis was only 2.2 times as large. Excretion of potassium and creatinine was only slightly increased by either substance. The elimination of urea was increased by both substances to the same degree as the corresponding increase in diuresis.     

Synthesis, natriuretic, antikaliuretic and antimagnesiuretic properties of an acidic triamterene derivative.

2,4,7-Triamino-6-(4-methanesulfonamidophenyl) pteridine (RPH 3048) is a new acidic triamterene derivative. Relevant physico-chemical constants were determined (solubility at pH 7.4 = 3.7 mg/l; logP at pH 7.4 = 0.2) and pharmacokinetic as well as pharmacodynamic properties were investigated, using male Wistar rats. After intravenous application of the test substances urine was collected, its volume and electrolyte composition determined, and the urine recovery of the drugs was analysed. The comparison of RPH 3048 with triamterene (CAS 396-01-0) revealed almost equipotent natriuretic and potassium-retaining effects for both drugs and an additional relative magnesium-sparing activity of RPH 3048. The urine recovery of RPH 3048 after 6 h was higher (20.6%) than that of triamterene (12.9%). No metabolite of RPH 3048 could be detected in the urine whereas a triamterene metabolite was found. Due to its good solubility in alkaline medium RPH 3048 could be dissolved (at pH 11-12) and then administered intravenously together with a loop diuretic (furosemide). Urinary electrolyte excretion following administration of two different combinations of RPH 3048 and furosemide (combination A: 12.5 mumol/kg RPH 3048 and 25 mumol/kg furosemide; combination B: 25 mumol/kg RPH 3048 and 25 mumol/kg furosemide) was compared to urinary electrolyte excretion of a control group and a group only treated with furosemide (25 mumol/kg). The additional application of RPH 3048 reduced in both groups potassium and magnesium excretion to control level but did not compromise furosemide induced natriuresis. In contrast to earlier investigations these results suggest that it is possible to develop acidic triamterene derivatives with potent antikaliuretic effects.     

Distribution,elimination and effect of furosemide in normal subjects and in patients with heart failure

Summary After furosemide 40 mg i. v. its plasma concentration was significantly higher during an 8-hour period in 6 patients with left sided heart failure than in 8 normal subjects. The plasma clearance was significantly lower in the patients than in the normal subjects — 1.23 and 2.34 ml/kg/min, respectively. The apparently smaller volume of distribution in the cardiac patients (0.140 l/kg and 0.181 l/kg, respectively) was not significantly different. In the group of normal subjects, whose ages ranged from 27 to 74 years, no correlation was found between age and either plasma clearance or volume of distribution. In all the patients, the renal clearance of furosemide rose from the first to the second hour after the injection (average ± SD) — 39±17 and 77±51 ml/min. In normal subjects, the average values did not change — 116±79 and 117±54 ml/min. The urinary excretion of furosemide and a metabolite (probably a glucuronide) was measured in 16 individuals. 24-hour urines from all the subjects investigated contained between 20 and 30 mg unchanged furosemide (average 25.2 mg). In addition, between 2.7 and 11.2 mg (average 6.7 mg) furosemide was excreted as the metabolite in five patients who had been treated with furosemide for at least the preceding 6 months. An average of 0.8±0.8 mg of the metabolite was found in 11 subjects who had not previously been treated with furosemide.     

Comparison of the pharmacodynamic effects of furosemide and BAY g 2821 and correlation of the pharmacodynamics and pharmacokinetics of BAY g 2821 (muzolimine)

Summary In a biometrically planned, double-blind study on 12 Oedema-free male patients the saluretic effect of muzolimine 30 mg was compared with furosemide 40 mg. The plasma level of muzolimine was determined and correlated with its pharmacodynamics. In terms of excretion during the 12-hour observation period muzolimine 30 mg had as great a cumulative effect as furosemide 40 mg. There was a significant difference in the time-response curve. During the first two hours furosemide 40 mg had more saluretic effect than muzolimine 30 mg. Between two and four hours there was no significant difference between the two substances. Between four and six hours, however, muzolimine was somewhat more effective than furosemide, although the difference did not reach the level of significance. After 6 h there was no longer any difference between the two compounds. The half-life of the fall in concentration of muzolimine in plasma was 3.7 up to 10 h after its administration. The time-response curve of the increased urine excretion correlated well with the time course of the concentration of muzolimine in plasma.     

Absence of magnesium sparing effect of a single dose of triamterene in combination with frusemide in healthy male adults.

In a study of cross-over randomized design in 12 healthy volunteers we compared the effect on magnesium excretion after administration of single oral doses of frusemide 40 mg (F) and of frusemide 40 mg in combination with a single dose of triamterene 50 mg (F+T). F as well as F+T induced significant increases in volume, sodium and magnesium mean 24 h output as compared with 24 h renal excretion without medication. Addition of triamterene to frusemide significantly reduced the 24 h potassium excretion, but did not attenuate the excretion of magnesium. The time to reach the maximum magnesium excretion rate after F as well as after F+T administration was similar to that of the sodium excretion rate. We conclude that triamterene does not inhibit the magnesiuric effects of frusemide in healthy male adults.     

Pharmacokinetics of metformin after intravenous and oral administration to man

Summary The kinetics of¹⁴C-metformin have been studied in five healthy subjects after oral and intravenous administration. The intravenous dose was distributed to a small central compartment of 9.9±1.61 ( ±SE), from which its elimination could be described using three-compartment open model. The elimination half-life from plasma was 1.7±0.1 h. Urinary excretion data revealed a quantitatively minor terminal elimination phase with a half-life of 8.9±0.7 h. After the intravenous dose, metformin was completely excreted unchanged in urine with a renal clearance of 454±47 ml/min. Metformin was not bound to plasma proteins. The concentration of metformin in saliva was considerably lower than in plasma and declined more slowly. The bioavailability of metformin tablets averaged 50–60%. The rate of absorption was slower than that of elimination, which resulted in a plasma concentration profile of flip-flop type for oral metformin.     

The efficacy of a potassium-rich diet compared to diuretic treatment on the renal elimination of thallium in the rat

The influence of potassium retaining diuretic agents (K-canrenoate and triamterene) on the renal elimination of orally ingested thallium (48.9 mol = 10 mg/kg) in rats proved negligible, whereas in earlier studies we had demonstrated that furosemide significantly enhances the elimination of thallium from the body via the renal route.We could not establish a relationship between the elimination of potassium and thallium on the one hand and between the thalliuresis and the urine production under the influence of diuretic drugs on the other hand.In connection with our interest in the interaction between thallium and alkali-ions like potassium and sodium we also studied the influence of a sodiumrich and a potassium-rich diet on the rate of thallium elimination from the rat's body. When the animals were fed a potassium-rich diet, the amount of thallium excreted in 1 week was increased from 21% of the ingested dose (controls) to 57%. This considerable increase in thallium elimination was not further enhanced by simultaneous treatment with the most potent diuretic furosemide. In the present animal model the treatment with potassium-rich food (approximately 40 mmol KCl · kg^–1 · day^–1) is superior to the administration of furosemide, with respect to the acceleration of thallium elimination from the body.A sodium-rich diet, however, did not increase the rate of renal elimination of thallium and even inhibited the effect of furosemide in this respect. The mechanism underlying the influence of potassium and sodium on the renal elimination of thallium remains obscure. The relative and absolute amounts of sodium and potassium present in the diet might be of importance with respect to the explanation of species differences observed in the sensitivity towards the effects of thallium and also in the therapy of thallotoxicosis.Some of the results have been communicated at the Congress of the European Society for Toxicology at Berlin, Federal Republic of Germany (June 1978)     

Tissue levels of cyclic nucleotides in the rat kidney after administration of furosemide

Summary In Sprague Dawlwy rats left kidneys were quickly frozen 6–35 min after intravenous injection of furosemide (0.5, 5 and 50 mg/kg) using a clamp precooled with liquid nitrogen. Cyclic adenosine-3:5-monophosphate (cAMP) extracted from the tissue was assayed by a binding test with cAMP dependent protein kinase from beef heart and cyclic guanosine-3:5-monophosphate (cGMP) with a cGMP dependent protein kinase from lobster tail (humarus vulgaris). Glomerular filtration rate (as inulin clearance) and sodium excretion were measured. Within the first 8 min 0.5 mg/kg furosemide increased urine volume and sodium excretion 3-fold. cGMP levels rose two and a half-fold whereas the cAMP content was not significantly changed. Higher doses of 5 and 50 mg/kg furosemide increased urine volume and sodium excretion further. These doses now increased cAMP levels from 3.12±0.31 to 11.3±0.91 and 12.1±0.13 pmol/mg dry weight, respectively (P<0.001). cGMP levels were elevated from 0.44 ±0.05 to 1.97±0.25 and 1.12±0.22 pmol/mg dry weight (P<0.001). 26 min after the administration of the diuretic, tissue levels of both nucleotides had returned to control values.These data do not support the idea that the cAMP-adenylcyclase-system is involved in the mechanism of diuretic action of furosemide.Part of this work was presented at the Xth Symposion of the Gesellschaft für Nephrologie, Innsbruck, 2.–5.10.1974     

Effect of probenecid on excretion and natriuretic action of furosemide

Summary Furosemide and inulin were given simultaneously by intravenous infusion to nine subjects over 2 h. The concentrations of sodium and of the two drugs in serum (free and protein bound) and in urine were followed during the infusion. In 6 male subjects the investigation was repeated after 3 days of oral treatment with probenecid 500 mg twice daily. Probenecid reduced the average ratio furosemide clearance/inulin clearance from 0.92 to 0.44. In experiments in which no probenecid had been given an average of 2% of the furosemide in urine was excreted by glomerular filtration. In vitro studies showed that the protein binding of furosemide was decreased in the presence of probenecid. The displacing effect of probenecid was confirmed in vivo, and during probenecid treatment glomerular filtration produced an average of 8% of the furosemide excreted by the kidney. The fraction of furosemide excreted by tubular secretion decreased during probenecid treatment from 98.0±0.6% to 91.7±5.6% (p<0.05). Prior to administration of probenecid, the fraction of the filtered sodium recovered from the urine during furosemide administration was 24.7%. Probenecid reduced that fraction to 21.0% (p<0.05). The excretion rate of furosemide appeared to be a better predictor of the natriuretic effect than its plasma concentration. Probenecid caused a significant change (p<0.05) in the regression line relating the log plasma concentration to the natriuretic effect, but it had no effect on the regression line relating the log urinary excretion rate of furosemide to its natriuretic effect. Although the decrease in the furosemide excretion rate during probenecid treatment averaged 25%, the sodium excretion rate was reduced by less than 15%. It is suggested that the natriuretic effect of furosemide is more pronounced if the furosemide molecules enter the tubular lumen at a more proximal level, and it is strongest if they do so by filtration through the glomerulus.     

Pharmacodynamics and pharmacokinetics of furosemide combinations with potassium-retaining and thiazide-like diuretics: Clearance and micropuncture studies

Summary The interaction between furosemide on the one hand and hydrochlorothiazide, tizolemide, amiloride and triamterene on the other was studied by clearance and micropuncture techniques in rats. Simultaneous administration of furosemide with hydrochlorothiazide and tizolemide distinctly increased the natriuresis compared to that induced by furosemide alone, whereas the potassium excretion diminished. In contrast, amiloride and triamterene primarily decreased furosemide-induced fractional potassium excretion by about 30%, whereas sodium excretion increased only slightly compared to that produced by furosemide alone. Hydrochlorothiazide and triamterene significantly decreased furosemide secretion and changed its pharmacokinetics. Furosemide plasma concentration increased, thus possibly prolonging the salidiuretic effect. Amiloride and tizolemide did not influence the secretion of furosemide at all.This paper is dedicated to Prof. Dr. med. Eberhard von Wasielewski on his 65th birthday     

Sublingual administration of furosemide: new application of an old drug

What is already known about this subject

• Furosemide is an effective diuretic, but its absorption may be too slow to allow oral treatment in certain patients.

What this study adds

• In healthy volunteers, sublingual administration is associated with a higher C_max, a higher bioavailability and a more accentuated initial natriuretic response than oral furosemide. Sublingual administration may offer advantages over oral administration of furosemide in certain clinical situations.

Background

In patients with decompensated heart failure, absorption of orally administered furosemide may be delayed, possibly leading to impaired pharmacodynamic effects. Sublingual administration may represent an alternative in such situations.

Methods

In a crossover study including 11 healthy men, 20 mg furosemide was administered intravenously, orally and sublingually on three different days. Pharmacokinetics and pharmacodynamics were assessed from repeated blood and urine samples.

Results

Compared with oral administration, sublingual administration was associated with 43% higher C_max[difference 215 ng ml⁻¹, 95% confidence interval (CI) 37, 392], a higher urinary recovery (8.9 vs. 7.3 mg, difference 1.6 mg, 95% CI 0.3, 2.9), an 28% higher AUC (difference 328 ng h⁻¹ ml⁻¹, 95% CI 24, 632) and a higher bioavailability of furosemide (59 vs. 47%, difference 12.0%, 95% CI −1.2, 25.2). Sodium excretion was higher after sublingual compared with oral administration (peak excretion rate 1.8 vs. 1.4 mmol min⁻¹, P < 0.05), whereas urine volume did not differ significantly between the two application modes. In comparison, intravenous administration showed the expected more rapid and intense response.

Conclusion

Sublingually administered furosemide tablets differ in certain kinetic and dynamic properties from identical tablets given orally. Sublingual administration of furosemide may offer therapeutic advantages in certain groups of patients.     

Pharmacokinetics and oral bioavailability of pyridostigmine in man

Summary The pharmacokinetics of pyridostigmine was evaluated after intravenous injection in two healthy male volunteers and after oral administration to five subjects. Plasma concentrations of pyridostigmine were determined after ion pair extraction from plasma and analysis by gas chromatography — mass spectrometry with chemical ionization, using d₆-pyridostigmine as internal standard. Degradation of pyridostigmine in vitro was compensated for by use of the deuterated internal standard and by rapid cooling and separation of plasma after blood sampling. After intravenous administration of pyridostigmine 2.5 mg the plasma elimination half-life was 1.52 h, the volume of distribution was 1.43 l/kg and the plasma clearance 0.65 l/kg × h. The pharmacokinetic constants were very similar after oral administration of pyridostigmine 120 mg; the elimination half-life was 1.78±0.24 h, the volume of distribution 1.64±0.29 l/kg and the plasma clearance was 0.66±0.22 l/kg × h. The bioavailability was calculated to be 7.6±2.4%. When pyridostigmine was taken together with food, the time to reach the peak plasma concentration was prolonged from 1.7 to 3.2 h. Bioavailability, however, was not influenced by concomitant food intake. Steady-state plasma concentrations of pyridostigmine were measured in myasthenic patients on their ordinary dose schedule of cholinesterase inhibitor drugs. More than a seven-fold difference in steady-state plasma concentration was found between patients taking approximately the same daily dose of pyridostigmine.     

Absence of a clinically significant interaction between theophylline and furosemide

Summary In new of previous contradictory results, the possible interaction between the loop diuretic furosemide and theophylline was re-evaluated in 12 healthy volunteers with a steady-state plasma theophylline level.Two doses of furosemide 20 mg at a 4 h interval did not influence the steady-state plasma concentration of theophylline despite causing a moderate diuresis. Urinary recovery of theophylline and its metabolites amounted to 106±21% of the dose without furosemide and 96±19% of the dose with furosemide, demonstrating that there was no influence on the enteral absorption of theophylline of the furosemide treatment. After the first dose of furosemide the fractional renal clearance (CL_R1) of theophylline (fractional = hourly sampling period) changed in parallel with the urinary flow rate, without a significant difference between treatment with and without furosemide. After the second dose of furosemide, CL_R1 was increased in the first hour and then it declined to levels far lower than the control value.This unexpected result could explain the unchanged plasma concentration of theophylline during furosemide treatment.