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PubMed2004

Triamterene-beta-cyclodextrin systems: preparation, characterization and in vivo evaluation.

The purpose of this research was to improve the solubility and therefore dissolution and bioavailability of triamterene, a poorly water soluble diuretic, by complexation with beta-cyclodextrin. Triamterene has been reported to show low bioavailability after oral administration, with wide intersubject variation. This study presents the formulation of solid dispersions of triamterene with beta-cyclodextrin--by cogrinding, kneading, and coevaporation, using low pH conditions--and their characterization, evaluation of improvement in dissolution profiles, and in vivo advantage. Phase solubility studies indicated complex with possible stoichiometry of 1:1 and a stability constant of 167.67 M(-1). The solid dispersions were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance, x-ray diffraction, and differential scanning calorimetry studies. The characterization studies confirmed inclusion of the phenyl ring of triamterene within the nonpolar cavity of beta-cyclodextrin in the coevaporate. Remarkable improvement in in vitro drug release profiles in 0.1N HCl and pH 6.8 phosphate buffer was observed with all dispersions, especially the coevaporate. The coevaporate, when administered orally in rats, also exhibited improved in vivo activity, as measured by net sodium ion excretion, as compared with triamterene powder. Thus, coevaporation of the drug and beta-cyclodextrin from acidified alcohol provide the optimum condition for inclusion complexation to give a binary system with remarkable improvement in in vitro drug release profile and in vivo performance.

Animals↗
PubMed1975

[Animal experiments on the effect of triamterene and amiloride on heart and circulation and the toxicity of digoxin (author's transl)].

1. In anesthetized cats 2,4,7-triamino-6-phenyl-pteridine (triamterene) (5 mg/kg i.v.) causes a short-lasting increase in blood pressure, a decrease in heart rate, whereas the contractility (see article) remains unchanged. N-Amidino-3,5-diamino-6-chloropyrazinecarboxamide (amiloride) (5 mg/kg i.v.) causes a fall of blood pressure, an increase in heart rate, and an increase in contractility. 2. In cats the i.v. toxicity of digoxin is diminished by pretreatment with triamterene or amiloride; the arrhythmias and the cardiac arrest are significantly delayed in the course of an infusion of digoxin. In guinea-pigs a pretreatment with triamterene only delays the arrhythmias but not the lethal effect of digoxin or g-strophanthin. 3. In the isolated atria of the guinea-pig triamterene and amiloride (5 mug or 50 mug/ml) lowers the rate of contraction and prolongs the functional refractory period. The force of contraction is increased by triamterene and diminished by amiloride.

Amiloride↗
PubMed1992

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.

Animals↗
PubMed1976

An experimental and clinical pharmacological study of the influence of triamterene on the diuretic and saluretic properties of furosemide xantinol.

The diuretic and saluretic effect of furosemide xantinol administered alone and mixed with different amounts of 2,4,7-triamino-6-phenylpteridine (triamterene) have been investigated in rat and man. The presence of triamterene resulted in a dose dependent inhibition of furosemide xantinol induced diuresis in both species. It was necessary to reduce the amount of triamterene present in the mixture to approximately half that of the one theoretically required according to considerations of the recommended therapeutic doses of the two diuretics before significant inhibition was avoided. Nevertheless, this reduced amount of triamterene proved sufficient to inhibit the distal tubular exchange of Na+ for K+ and H+ and a mixture formulated to give the ratio of 40 mg furosemide xantinol (as base) plus 25 mg triamterene (Salidur) was shown to produce a smooth but efficient loss of water and Na+ in the absence of detectable kaliuresis or reduction in urinary pH, thereby reducing the usual risk of inducing hypokalaemic alkalosis.

Adult↗
PubMed1989

Comparative efficacy and bioequivalence of a brand-name and a generic triamterene-hydrochlorothiazide combination product.

The clinical efficacy, safety, and bioavailability of a generic triamterene-hydrochlorothiazide product were compared with those of Dyazide. Thirty patients who had a diagnosis of nonlabile essential hypertension and who were receiving Dyazide (triamterene 50 mg and hydrochlorothiazide 25 mg) were continued on Dyazide maintenance for 16 days to determine the stability of blood pressure control and serum chemistry values. After this baseline period, the subjects were randomized to receive either Dyazide or a generic version for 21 days. They were then crossed over to receive the opposite product for another 21 days. Blood pressures were monitored throughout the study period, and blood samples were taken for measurement of serum electrolytes and of serum triamterene and its major metabolite, hydroxytriamterene sulfate. Hydrochlorothiazide was assayed in 24-hour urine samples. There were no statistically significant differences between regimens in recumbent and standing mean diastolic blood pressures or in mean concentrations of serum potassium, chloride, glucose, creatinine, and uric acid. Area under the concentration-time curve from 0 to 24 hours after drug administration, maximum concentration in serum, and time to achieve maximum concentration in serum did not differ significantly between regimens for triamterene and hydroxytriamterene sulfate. Similarly, there were no significant differences in excretion, maximum rate of excretion, and time to achieve maximum rate of excretion for urinary hydrochlorothiazide. Patients treated with a brand-name fixed-combination product containing triamterene 50 mg and hydrochlorothiazide 25 mg were given a generic formulation without loss of therapeutic efficacy or development of toxicity.

Adolescent↗
PubMed1988

Maintenance of potassium balance during long-term diuretic therapy in chronic heart failure patients with thiazide-induced hypokalemia: comparison of potassium supplementation with potassium chloride and potassium-sparing agents, amiloride and triamterene.

The relative efficacy of potassium chloride, amiloride and triamterene in maintaining potassium and magnesium balance was evaluated in 23 hypokalemic (S-K less than or equal to 3.5 mmol/l) patients with chronic heart failure receiving diuretic therapy. Amiloride and triamterene were administered in a randomized, crossover manner, followed by potassium chloride in an open manner. During a 5-month treatment with hydrochlorothiazide 50 mg twice/day, potassium chloride 1 g twice/day was not as effective as amiloride 5 mg or triamterene 75 mg twice/day in maintaining serum potassium and magnesium and total-body potassium, while amiloride and triamterene seemed to be equally effective. During all three supplementations, a decrease in serum potassium to a hypokalemic level was observed in some patients. The need for higher doses of potassium chloride, amiloride and triamterene was clearly concentrated to the same patients, and correction was easily reached by increasing the respective doses.

Adult↗
PubMed1988

Mechanism of triamterene transfer across the human placenta.

The diuretic, triamterene, had been regarded to be a drug which was actively transported by the placenta from fetus to mother. In the present study, the transfer of triamterene across the isolated perfused human placenta was examined. Placentas obtained at cesarean section were perfused for up to 2 hr from both maternal and fetal sides in either single-pass or recycling constant flow systems. In single-pass experiments, the placental clearance of triamterene (400 ng/ml) from mother to fetus or from fetus to mother was examined (n = 8). Antipyrine (20 micrograms/ml) and l-leucine (0.25 mM) were used as reference compounds. The transplacental clearance index (i.e., clearance relative to antipyrine clearance) of triamterene from mother to fetus (0.85 +/- 0.10) was similar to the clearance index from fetus to mother (0.74 +/- 0.08, P greater than .10), indicating rapid transfer across the placenta, but no active fetal to maternal transport. In contrast, the l-leucine clearance index from mother to fetus (0.62 +/- 0.05) was substantially greater than that from fetus to mother (0.27 +/- 0.03, P less than .01), consistent with active maternal to fetal transport. In recycling experiments (n = 5), with test compounds added in equal concentration to both maternal and fetal circuits, the equilibrium fetal/maternal perfusate concentration ratios were 1.41 +/- 0.02 for l-leucine and 0.98 +/- 0.01 for antipyrine. The slightly lower value for triamterene (0.92 +/- 0.02) probably reflected minor differences in protein binding between maternal and fetal circuits.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretics↗
PubMed1986

[The antitoxic action of triamterene in cardiac glycoside poisoning].

The antagonistic effect of triamterene on the toxicity of cardiac glycosides was investigated in conscious rabbits using the infusion method. Pretreatment with triamterene (5 mg/kg and 10 mg/kg) significantly reduces the ouabain toxicity indicated by an increase of the dose producing arrhythmia (from 61 +/- 14 to 121 +/- 17 and 178 +/- 22 micrograms/kg, resp.) and lethality (from 114 +/- 18 to 236 +/- 5 and 329 +/- 11 micrograms/kg, resp.). The triamterene induced increase of plasma potassium concentration may contribute to the antitoxic effect, however, the effect persisted after the decrease of plasma potassium concentration (by addition of NaHCO3) to pretreatment values. Under the influence of digitoxin the antitoxic effect of triamterene (10 mg/kg) is also demonstrated by the delayed appearance of arrhythmias (113 +/- 3 min compared to 78 +/- 5 min) and of lethality (125 +/- 4 min compared to 92 +/- 6 min). Triamterene is not only a prophylactic but also a curative antitoxic agent in the digitalis intoxicated rabbit.

Animals↗
PubMed1986

Competitive inhibition of folic acid absorption in rat jejunum by triamterene.

Triamterene, a diuretic agent, has been reported to cause megaloblastic anemia in some patients. Because this drug is a pteridine derivative, we investigated its effect on folic acid absorption in the rat jejunum. In an in vivo intestinal loop method, triamterene inhibited the intestinal absorption of folic acid in a dose-dependent fashion, with 50% inhibition of systemic absorption occurring at a luminal concentration of 0.01 mmol/L of triamterene. Kinetic analysis using the influx chamber method demonstrated that triamterene is a competitive inhibitor of intestinal folate transport, with a Ki of 0.125 mmol/L. Because therapeutic doses can result in luminal concentration of the drug approximating or exceeding the Ki, the interaction between triamterene and folate absorption is potentially of clinical interest.

Animals↗
PubMed1978

[Pharmacological effects of phase-I- and phase-II-metabolites of triamterene (author's transl)].

Since triamterene (TA) is rapidly metabolized to hydroxytriamterene (OH-TA) and then to its sulfuric acid ester (OH-TA-ester) the question arose whether the metabolites are still effective on ion transport as is triamterene. The effect of the metabolites was studied in microperfusion experiments on the rat submaxillary duct, which resembles the distal nephron and is considered the site of action of triamterene. Added to the lumen the phase-I- as well as the phase-II-metabolites decreased reabsorption of Na+, secretion of K+, and yielded an accumulation of HCO3-. These effects of the metabolites were produced by equimolar concentrations and are almost identical to those of native triamterene. In conclusion, the phase-II-metabolite must be considered to be essentially responsible for the natriuresis and antikaliuresis observed after oral administration of triamterene.

Animals↗
PubMed1982

[Pharmacokinetics of xipamide and triamterene in healthy probands].

Simultaneous detection of 4-chloro-5-sulfamoyl-2',6'-salicyl-oxylidide (Xipamide) and 2,4,7-triamino-6-phenyl-pteridine (Triamterene) in urine specimen of healthy volunteers was achieved by means of a new high performance liquid chromatography (HPLC) method. Pharmacokinetics of both substances in combination (Neotri, dose ratio xipamide: triamterene = 1:3) did not significantly differ from those of the sole substances. Peak urine elimination of unaltered xipamide was 2.5 +/- 0.7 mg/h when given alone and 2.0 +/- 0.7 mg/h in the presence of triamterene. The data for the triamterene excretion were 0.7 +/- 0.1 mg/h and 1.0 +/- 0.3 mg/h, respectively within 1-3 h post application. Assuming a two-compartment pharmacokinetic model the terminal elimination half-lives of unchanged xipamide were 5.3 +/- 1.9 h (monosubstance) and 4.0 +/- 0.6 h (combination). The corresponding data for unchanged triamterene were 6.4 +/- 1.3 h (monosubstance) and 5.5 +/- 1.8 h (combination).

Adult↗
PubMed1978

Handling of triamterene by the isolated perfused rat kidney.

Quantitative studies on the renal handling of [3H]triamterene were performed in an isolated perfused rat kidney with near normal function and in an isolated kidney with negligible filtration rate, but preserved perfusate flow rate. The excretory pattern for [3H]triamterene is compatible with that of other weak bases such as quinine and quinacrine. Tubular secretion of [3H]triamterene is strongly inhibited by anoxia and iodoacetate. Tubular reabsorption of [3H]triamterene becomes pronounced when the urine is alkaline. Clearances were reported with and without correction for perfusate albumin binding which is about 75%. Bidirectional transport processes are operative in that [3H]triamterene is secreted by the renal tubule and passively diffuses back across the tubular epithelium by a pH-dependent mechanism.

Animals↗
PubMed1982

[Triamterene and renal calculi].

The authors report the detailed analysis of 4 calculi containing triamterene observed between 1979 and 1981. The composition of drug layers is almost the same in the 4 calculi and shows a mixture of triamterene (estimated at 35% of iatrogenic components) and 7 metabolites among them p-hydroxy-triamterene (5-10%) and mainly p-hydroxytriamterene estersulfate (40-55%). The authors hypothesize a metabolic or physicochemical relation between triamterene and uric acid which are frequently associated in these calculi that represent 0.4% of all lithiasis. An estimated 150 to 200 calculi with triamterene are probably eliminated though not detected every year in France. The interest of a fine analysis of calculi by appropriate physical methods, such as infrared spectrometry, is emphasized.

Adult↗
PubMed1980

[Drug induced nephrolithiasis: observation of an oxalate and hydroxylated triamterene stone (author's transl)].

A 54-year old man who had been taking triamterene (150 mg daily) over a period of 8 months, passed a 3 mm stone partly coated with mustard-colored substance. Metabolic evaluation showed only mild-hyperoxaluria. Through IR spectrography after microdissection, thin-layer chromatography, UV light examination, and mass spectrometry, the stone if found to consist of 70% whewellite, 5% protein, 5% carbapatite and 20% triamterene and hydroxylated triamterene, and perhaps also the sulfate conjugate of this metabolite. In spite of the few number of observations (two cases have been reported previously), triamterene seems likely to induce stone formation, both alone and associated with urate or oxalate, and triamterene should be used cautiously in patients with a predisposition for nephrolithiasis.

Humans↗
PubMed1984

Liquid chromatographic analysis of triamterene and its major metabolite, hydroxytriamterene sulfate, in blood, plasma, and urine.

The first rapid and highly sensitive high-performance liquid chromatographic (HPLC) assay for triamterene, hydroxytriamterene, and hydroxytriamterene sulfate is reported. Plasma samples were processed by protein precipitation, while urine was used untreated. Three different solvent systems were used to analyze (a) triamterene in plasma (30% acetonitrile, pH 4.0; internal standard: furosemide; sensitivity limit: 1 ng/mL); (b) hydroxytriamterene and hydroxytriamterene sulfate in plasma (12% acetonitrile, pH 5.5; internal standard: cefamandole; sensitivity limits: 20 and 2 ng/mL, respectively) and (c) triamterene, hydroxytriamterene, and hydroxytriamterene sulfate in urine (13% acetonitrile, pH 5.3; internal standard: hydroflumethiazide; sensitivity limits: 0.04 microgram/mL, 0.5 microgram/mL, and 0.1 microgram/mL, respectively). Fluorescence detection of compounds was performed at 365-nm excitation and 440-nm emission wavelengths. Recovery of triamterene and its metabolites from plasma was complete, and calibration curves were linear. Intraday variation was less than 6% except for the lowest plasma concentration. The assay procedure has already been used in several pharmacokinetic studies.

Chromatography, High Pressure Liquid↗
PubMed1989

Physicochemical and structural studies of triamterene.

It has been shown by several physicochemical techniques that the existence of different crystal forms of triamterene, as well as the crystalline products from different solvents with distinct differences in melting points, does not necessarily imply polymorphic crystal forms. The crystalline structure for triamterene is reported herein, revealing a N,N-dimethylformamide molecule and a water molecule within the crystal lattice. Triamterene crystallizes in a face-centered orthorhombic space group, Fdd2 (#43), when grown from aqueous solutions of dimethylformamide (N,N-DMF). In addition, the asymmetric unit contains a partially occupied molecule which is situated on a crystallographic twofold axis. Weak hydrogen bonding occurs between atoms O(1) and N(7), with a distance of 2.66 A, O(1) and N(5) with a distance of 2.96 A, O(2) and N(1), at two different symmetry sites of 2.99 A, and N(2) and N(7), with a distance of 2.91 A. The different solvated crystalline triamterene specimens have different melting points depending on organic solvation, water, or both.

Chemical Phenomena↗
PubMed2001

Simultaneous direct determination of amiloride and triamterene in urine using isopotential fluorometry.

A method for the simultaneous fluorometric determination of two diuretics in urine is proposed. The combination of matrix isopotential synchronous fluorescence (MISF) and first derivative techniques provides good analytical results. MISF spectra are obtained by calculating the isopotential trajectory in the three-dimensional fluorescence spectrum for a urine solution. In the spectral contour, the trajectory is taken to be the portion of the line that passes by the fluorescence maxima of both diuretics (lambda(ex) = 365 and lambda(em) = 413 nm for amiloride and lambda(ex) = 365 and lambda(em) = 437 nm for triamterene). Because contour lines connect points of identical intensity and the trajectory is part of a contour line, it is called "isopotential." Analyses was carried out in a 1/1 (v/v) ethanol/water mixture, using an apparent pH of 6.3 provided by 0.01 M sodium/citrate citric acid buffer. Urine samples are diluted 50 times and provide linear calibration plots at amiloride and triamterene concentrations up to 320 and 100 ng mL(-1), respectively. The goodness of the analytical signal was checked by using variance analysis. Signals recorded throughout the calibration range were subjected to three calibrations per each analyte, both in the absence and in the presence of variable amounts of the other analyte. Differences between individual calibrations and slopes were compared with those within individual calibrations. Based on the results, triamterene and amiloride can be accurately quantified in the presence of each other. The limit of detection calculated according to Clayton who uses error propagation throughout the calibration curve and a noncentralized security factor was 16.8 and 2.4 ng mL(-1) for amiloride and triamterene, respectively.

Amiloride↗
PubMed1983

Delayed elimination of triamterene and its active metabolite in chronic renal failure.

The kinetics of triamterene and its active phase II metabolite were studied in 32 patients with various degrees of impaired renal function; the creatinine clearances ranged from 135 to 10 ml/min. The area under the plasma concentration-time curves (AUC) for triamterene were not influenced by kidney function, but the AUCs for the effective metabolite OH-TA-ester were significantly elevated in renal failure, indicating accumulation of the metabolite. Urinary recovery of triamterene and its metabolite over a 48 h collection period was significantly reduced in renal failure. This is considered to be due to delayed urinary excretion, corresponding to reduced renal clearance. The renal clearance of the native drug exceeded that of the metabolite, because of their different protein binding, 55% for triamterene and 91% for the metabolite. The latter is eliminated almost exclusively via tubular secretion and extra-renal elimination is less important. Administration of this antikaliuretic is therefore considered hazardous in patients with impaired kidney function.

Adult↗