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PubMed1982

Pharmacokinetics of triamterene and its metabolite in man.

The pharmacokinetic profiles of triamterene and hydroxytriamterene sulfuric acid ester, the major metabolite of triamterene, were studied in six normal male volunteers using a newly developed specific HPLC analytical method. Following a 100 mg oral dose of triamterene, the plasma concentration time course of the sulfate conjugate parallels that of triamterene in all subjects, but concentrations of the metabolite were more than 10 times higher than unchanged triamterene concentrations at identical sampling times. Interestingly, the renal clearance of the sulfate conjugate was less than that of triamterene. These characteristic features of triamterene disposition were fitted to a compartment model incorporating a first-pass metabolic process. Unbound fractions of triamterene and metabolite in plasma were 0.39 and 0.10 (mean of 6 subjects), respectively. The low unbound fraction of the metabolite in plasma most probably accounts for the low renal clearance of the sulfate conjugate as compared with triamterene.

Adult↗
PubMed1991

Chronic diuretic therapy with moderate doses of triamterene is not associated with folate deficiency.

The diuretic drug triamterene has previously been shown to be a competitive inhibitor of folate absorption in the rat intestine (J Lab Clin Med 1986;108:272-6). We therefore investigated whether human subjects who are taking the drug on a long-term basis are at increased risk of folate deficiency. In each of two free-living populations, a study was performed to compare the folate status of triamterene users with those not taking the drug. The first population consisted of 272 elderly individuals not living in institutions who were participants in a nutrition status survey and who were taking a variety of antihypertensive medications; 32 of these individuals were daily users of triamterene. The hemoglobin concentration, red blood cell (RBC) count, and mean corpuscular volume (MCV) values were not significantly different between the triamterene users and nonusers. The female triamterene users had a slightly higher serum folate level than the female nonusers (p less than 0.04); a similar pattern was observed among the men, although the difference was not statistically significant. The second population consisted of 27 individuals attending a hypertension clinic; 18 subjects were taking 50 to 150 mg of triamterene per day and nine were taking antihypertensive drugs other than triamterene. The hemoglobin concentration, RBC count, MCV, serum folate values, and RBC folate values were found to not differ significantly between the triamterene users and the hypertensive controls (p greater than 0.05). These data suggest that chronic triamterene administration in individuals not living in institutions, at the doses examined in this study, is not associated with indications of folate deficiency.

Aged↗
PubMed1984

Triamterene kinetics and dynamics in cirrhosis.

Triamterene is extensively metabolized by the liver and undergoes important presystemic elimination in normal subjects after oral doses. We examined triamterene disposition in eight healthy controls and seven patients with cirrhosis and ascites. A specific and sensitive HPLC assay was used to measure concentrations of triamterene and of its major metabolite p-hydroxy-triamterene sulfate (OH-T-S). Apparent oral clearance of triamterene in controls averaged 1617 +/- 219 ml/min. Plasma concentration of OH-T-S was 7.2 +/- 1.1 times that of the parent compound (estimated by the ratio AUCOH -T-S/ AUCtriamterene ). Urinary recovery of OH-T-S accounted for 45% of the triamterene dose. There was 92% reduction in apparent oral clearance of triamterene (134 +/- 42 ml/min) in patients with cirrhosis. The ratio AUCOH -T-S/ AUCtriamterene fell to 0.55 +/- 0.2, and urinary recovery of OH-T-S accounted for only 15% of the dose. These changes in triamterene kinetics in patients with cirrhosis resulted in prolongation of its natriuretic effect, which lasted for up to 48 hr, whereas it was only 8 hr in the controls. These observations reinforce the concept that cirrhosis is associated with a markedly impaired disposition of drugs that have a large first-pass effect.

Adult↗
PubMed1986

Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene.

A chronic-dosing pharmacokinetic study was carried out in six healthy subjects to examine the potential for cimetidine to reduce the CLR and CLH of triamterene. Blood and urine samples were collected frequently for 24 hours after dosing with triamterene alone (100 mg/day) for 4 days and concomitant cimetidine (400 mg twice daily) for an additional 4 days. Cimetidine significantly reduced the clearance of triamterene by hydroxylation by 32% (P less than 0.016) and the CLR of triamterene by 28% (P less than 0.063), with no change in its protein binding. The CLR of the active sulfate conjugate of triamterene was not altered by cimetidine. There was a reduced recovery of triamterene and its metabolites in urine after cimetidine, suggesting a decreased absorption. These results are consistent with cimetidine inhibiting cytochrome P-450 enzymes in the liver and also competing with triamterene for renal tubular secretion. Despite the pharmacokinetic interaction, cimetidine caused minimal alteration to the natriuretic and antikaliuretic effects of triamterene.

Administration, Oral↗
PubMed1976

On the mechanism of action of triamterene: effects on transport of Na+, K+, and H+/HCO3- -ions.

The rat salivary duct epithelium, which actively transports Na+, K+, and H+/HCO3- in a manner similar to renal distal tubules, was used as a model tissue to study the mechanism of action of triamterene on electrolyte transport. 10(-4) M triamterene completely blocked Na+ resorption and lowered net K+ secretion to half that of controls, whereas HCO3- accumlated in the lumen, probably due to a decrease in H+ secretion. The rates of K+ and H+/HCO3- transport in the presence of triamterene did not differ from those determined after omission of Na+ from the luminal fluid. This was considered to be evidence against a direct action of triamterene on transport of K+ and H+/HCO3-. Triamterene rapidly and reversibly reduced the transepithelial electrical potential difference. This was due to almost complete abolition of Na+ conductance of the luminal membrane at 10(-4) M triamterene, whereas K+ conductance was not altered. Triamterene, administered in vitro from the interstitial side of the isolated duct epithelium was ineffective even at the highest concentrations. The activities of the Na-K-ATPase, the Mg-ATPase and the microsomal HCO3-ATPase were influenced by 10(-4) M triameterene in a similiar fashion. These effects were clearly demonstrated only in the homogenate of the duct tissue and not in intact cells in the isolated duct preparation. Therefore they were considered unspecific. The transport studied demonstrate a primary effect of triamterene on Na+ entry from lumen to cell. Influences on net K+ and H+/HCO3 transport are secondary consequences of functional coupling between movement of Na+ and movement of K+ and H+ across the luminal cell membrane.

Adenosine Triphosphatases↗
PubMed1990

Hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy. Protection by conventional doses of spironolactone but not triamterene.

Salbutamol (Albuterol) and diuretics are commonly prescribed together in patients with airflow obstruction and are associated with electrocardiographic effects. We have now investigated whether the use of potassium-sparing drugs might prevent the ECG sequelae of such combined therapy. Ten healthy subjects received seven days of randomized treatments with: placebo, bendrofluazide (5 mg), bendrofluazide plus triamterene 50 mg (conventional dose), or triamterene 200 mg (high dose), and bendrofluazide plus spironolactone (100 mg). Potassium and ECG responses to inhaled salbutamol, 2 mg, were measured after each treatment period. The T-wave flattening in response to bendrofluazide and salbutamol (0.24[CI, 0.19 to 0.29]mV) was attenuated by the addition of triamterene, 200 mg (0.33[CI, 0.28 to 0.37]mV; p less than 0.05) and spironolactone 100 mg (0.42[CI, 0.37 to 0.47]mV; p less than 0.01), but not by triamterene 50 mg (0.25[CI, 0.20 to 0.30]mV). Spironolactone and high dose triamterene also diminished the frequency of U waves and ST depression. The ECG effects mirrored hypokalemic responses which were also blunted by high dose (p less than 0.01) but not low dose triamterene, as well as by spironolactone (p less than 0.001). Thus, the use of high dose triamterene and spironolactone protected against the hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy, whereas a conventional dose of triamterene had no effect. These findings may be important in the prevention of a potentially dangerous interaction in susceptible patients taking this combination of drugs.

Adult↗
PubMed1976

On the action of triamterene on isolated cell membranes.

Recently there have been recurring reports on extrarenal and expecially on antiarrhythmic effects of triamterene, the latter ones being observed particularly in cases of digitalis intoxication. Considering the digitalis-antagonistic effects, which are also observed in the course of experimental investigations, it was assumed that triamterene, a potassium-saving diuretic, displaces cardiac glycosides from their binding sites in cardiac membranes. The binding of [3H]-g-strophanthin ([3H]-ouabain) and the activity of the (Na+ + K+)-ATPase in the presence of different concentrations of triamterene have been studied with isolated cardiac cell membranes (human; bovine) and human erythrocyte membranes. Inhibition of the binding of the cardiac glycoside and the enzyme activity was only observed for very high concentrations of the active component. These observations are indicative of non-specific effects. Triamterene applied in the presence of different concentrations of strophanthin (10(-9)--5 X 10(-7) M) did not display protective effects on the (Na+ + K+)-ATPase activity. In experiments aimed at chromatographic separations, it could be shown that [3H]-triamterene binds to membrane proteins different from those binding [3H]-g-strophanthin, the latter having been shown to be present in the (Na+ + K+)-ATPase containing fraction. From the results of these experiments it may be concluded that there is no interaction between triamterene and strophanthin on the membrane bound receptor for the cardiac glycoside. [3H]-Triamterene shows concentration dependent binding to cell membranes. This binding is affected to different degrees by Mg++, K+, Na+ and Ca++. The binding sites show low affinity but high binding capacity for triamterene. The significance of this fact remains to be established.

Adenosine Triphosphatases↗
PubMed1979

The effect of triamterene upon the rat kidney plasma membrane Na-K-ATP-ase activity.

Triamterene (2,4,7-triamino-6-phenylpteridine) is a potassium-sparing diuretic whose mechanism of action is not clear. Experiments were performed to study the effect of triamterene upon the activity of Na-K-ATP-ase in the kidney plasma membranes. This enzyme, dissolved within the membrane bilayer, has been considered to be a biochemical vehicle for the active transport of sodium across the cell membrane. Intact and adrenalectomized rats were subjected to a five-day treatment with triamterene in a daily dose of 1.5 mg/100 g body weight. Triamterene was also administered to a group of intact, salt-loaded, rats. The activity of Na-K-ATP-ase in the kidney plasma membranes of intact and adrenalectomized rats treated with triamterene was decreased by 22.4% (p less than 0.05) and 37.2% (p less than 0.05), respectively. The activity of Na-K-ATP-ase in the renal plasma membranes of intact, salt-loaded, rats underwent greater decrease--63% (p less than 0.05). If the decreased activity of Na-K-ATP-ase in the kidney plasma membranes of rats treated with triamterene manifested the diuretic action of triamterene, results obtained in adrenalectomized rats would suggest that triamterene acts directly on the kidney, not via the adrenal glands.

Adrenalectomy↗
PubMed1983

[Saluretic and diuretic effects of xipamide-triamterene combinations in varying dose ratios in rats].

The saluretic and diuretic properties of 4-chloro-5-sulfamoyl-2',6'-salicyloxylidide (xipamide) and 2,4,7-triamino-6-phenyl-pteridine (triamterene) were determined in rats following sole and combined application in various dosages and dose ratios. Xipamide dosages ranged from 0.01-30 mg/kg body weight. Xipamide, when given alone, revealed a significant dose-dependent increase in sodium excretion and urine volume compared to control animals even in the smallest dose to be tested (0.01 mg/kg). Triamterene as sole agent led to an increased sodium and water excretion when given in a natriuretic threshold dose of approximately 1.0 mg/kg. Potassium excretion was slightly enhanced following xipamide application and decreased significantly with triamterene treatment. The combined application of xipamide and triamterene in dose ratios of 1:1-1:4 (xipamide/triamterene) resulted in an increased sodium excretion which was almost additive following high triamterene dosages. Potassium elimination decreased significantly when threshold triamterene dosages were added. High triamterene dosages in all dose ratios of the combined application resulted in potassium levels which only could be registered following sole triamterene application.

Animals↗
PubMed2001

The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study.

Diuretics are a frequent cause of adverse drug effects in the elderly, many times involving drug-drug interactions. In addition, multiple chronic diseases, age-dependent pharmacokinetic and pharmacodynamic changes, and a decreased homeostatic capacity often complicate diuretic therapy in the elderly. The pharmacokinetics (area under the plasma concentration-time curve: AUC; peak concentration in plasma: c(max); time to reach peak concentration: t(max); terminal half-life: t(1/2)) and pharmacodynamics (urine flow rates and renal excretion rates of Na(+) at 1, 3, and 6 h after oral administration) of a fixed combination of 25 mg bemetizide and 50 mg triamterene were investigated in 15 elderly patients (age 70-84 years) and 10 young volunteers (age 18-30 years) after a single dose (day 1) and after multiple doses (at steady state, day 8). Compared with the young volunteers, mean plasma concentrations of bemetizide, triamterene, and the active triamterene metabolite were significantly higher in the elderly volunteers. These elevated plasma levels occurred after single dose and were even more pronounced after multiple dose in the elderly. While plasma concentrations and AUC of bemetizide, triamterene, and the active metabolite of triamterene were increasing in correlation to age of subjects and duration of therapy, urine flow and renal Na(+) excretion rates were decreasing at the same degree. At steady state conditions, practically no effect on urine flow and Na(+) excretion rates could be observed in the elderly patients (in contrast to the young volunteers) for the first 8 h after administration of bemetizide and triamterene. The lower the measured (endogenous) creatinine clearance was in all subjects, the higher were the plasma concentrations of bemetizide and triamterene, and the lower was the effect on pharmacodynamics (i.e. urine flow and renal Na(+) excretion rates). The glomerular filtration rate, known to be lower in the elderly (a priori), was apparently decreased at higher levels of bemetizide and triamterene in the elderly, which may explain why there was no diuretic and saluretic effect after multiple dose in the elderly patients.

Journal Article↗
PubMed1991

Antiarrhythmic properties of triamterene derivatives in the coronary artery ligated rat model.

Triamterene and several triamterene derivatives were tested for antiarrhythmic activity in the coronary artery ligated and reperfused (CAL-R) rat. The class-III antiarrhythmic drugs (+/-)-sotalol and amiodarone, the class-I antiarrhythmics lidocaine and quinidine as well as the potassium sparing diuretic amiloride were used as reference drugs. Triamterene at the highest dose (30 mumol/kg) revealed a 100% protection against ventricular fibrillation (VF), whereas at 10 mumol/kg no antiarrhythmic activity for triamterene could be found. For compound 4 (10 mumol/kg) a 75% protection against VF could be demonstrated, while 2, 3, and 5 revealed only a 25% protection. Compared to the reference drugs, triamterene and the derivatives 2-5 are more potent than (+/-)-sotalol, but less potent than lidocaine, quinidine and amiodarone. For amiloride as well as for the potent potassium retaining triamterene derivative 6 no antiarrhythmic activity could be shown. Therefore, we conclude different mechanisms responsible for the potassium sparing and antiarrhythmic properties of triamterene and its derivatives.

Animals↗
PubMedDate not supplied

Bioavailability of bemetizide and triamterene from a combination formulation.

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (p less than 0.01) from that from a tablet containing 25 mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3 ng ml-1) was lower than that after administration of bemetizide alone (87.9 ng ml-1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml-1) was higher than and significantly different (p less than 0.001) from that after administration of triamterene alone (15.7 ng ml-1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.

Adolescent↗
PubMed1981

Antifolate effect of triamterene on human leucocytes and on a human lymphoma cell line.

The inhibitory effect of triamterene and its metabolites on human leucocyte dihydrofolate reductase has been studied. Under test conditions with dihydrofolic acid 0.5 X 10(-5) M, triamterene 7 X 10(-5) M produced total enzyme inhibition, whereas the metabolites hydroxytriamterene and the sulphate ester of hydroxytriamterene were less effective inhibitors; at their maximum attainable concentration of 5 X 10(-5) M, dihydrofolate reductase was inhibited by 80% and 50%, respectively. Cultures of the BJAB-B95-8 human lymphoma cell line were incubated with various concentrations of triamterene. Because of their increased specific activity of dihydrofolate reductase, the cells were able to maintain normal DNA metabolism, as measured by the ratio of the incorporation rates of 3H-deoxyuridine and 3H-thymidine, as well as normal cell growth at 1 X 10(-6) M, and in some cases at 1 X 10(-5) M triamterene. At 8 X 10(-5) M triamterene, the strong inhibitory effect caused severe impairment of DNA metabolism and subsequently dissolution of the cell culture. The results are discussed in relation to the possible toxic side effects of long-term triamterene treatment in patients suffering from alcoholic cirrhosis, who may have impaired metabolism of triamterene and a concomitant severe folate deficiency.

Burkitt Lymphoma↗
PubMed1985

The true composition of kidney stones passed during triamterene therapy.

The potassium-sparing agent triamterene and its metabolites have been identified as components of kidney stones passed by patients receiving that drug. We have analyzed 66 such kidney stones by use of quantitative thin-layer chromatography. The stones contained not only the unchanged triamterene but also significant amounts of an intermediate metabolite, hydroxytriamterene, and large amounts of the sulfate ester of hydroxytriamterene. Of the stones 49 per cent contained less than 5 per cent triamterene and its metabolites, and no stone comprised 100 per cent triamterene-derived material. Of all the triamterene-related material unchanged triamterene dominated. However, the relative fractions of triamterene and hydroxytriamterene in the kidney stones exceeded the relative fractions of these 2 components in the urine.

Chromatography, Thin Layer↗
PubMed2000

Triamterene measurements in the aqueous humor of rabbits.

The kinetics of topical triamterene penetration were estimated from the time-course measurements of triamterene (in Dyazide) concentrations in the anterior chamber of six rabbits (n=12, left and right eyes). The two-compartment model of Jones and Maurice (1) was fitted to the measurements. We found the apparent elimination rate constant oftriamterene A = 0.33 +/- 0.12 hr(-1), the apparent absorption rate constant of triamterene B = 2.68 +/- 0.55 hr(-1), the cornea-aqueous transfer coefficient in reference to the corneal volume of triamterene kc.ca = 0.28 +/- 0.05 hr(-1), the loss coefficient of triamterene from the anterior chamber ko = 0.43 +/- 0.16 hr(-1) and the amount of triamterene in the cornea at time zero Mo = 483 +/- 125 ng/ml. The mean of ko = 0.43 hr(-1) is significantly lower (p = 0.04% using ZTEST) than the lower limit of aqueous loss coefficient = 0.58 hr(-1) usually found in rabbits (2). We conclude that Dyazide lowers the aqueous flow rate in the positive direction, considering glaucoma treatment. Peak triamterene concentration in the anterior chamber was P = 120 +/- 32 ng/ml. Half-life for elimination from the aqueous humor was T1/2 = 1.84 +/- 0.65 hr (Mean +/- SD).

Absorption↗
PubMed1979

Effect of triamterene on urinary excretion of immunoreactive prostaglandin E in essential hypertension.

The effect of triamterene on urinary excretion of prostaglandin E was studied, and the results were compared with those obtained with spironolactone. Urinary excretion of immunoreactive prostaglandin E was measured radioimmunologically. Triamterene was administered in a dose of 100 mg/day for 8 days to 7 patients with essential hypertension. Following the administration of triamterene, urinary prostaglandin E tended to increase. However, the increment was not significant. The lack of significant increase in urinary prostaglandin E excretion during the administration of triamterene contrasted with our previous finding with spironolactone, in which a significant increase in prostaglandin E excretion was observed on the first day of spironolactone administration. Urinary Na excretion and urinary Na/K ratio were significantly increased and urine volume also tended to increase following the administration of triamterene. Plasma renin activity and plasma aldosterone concentration were increased in all cases. However, there was no significant correlation between these parameters and urinary prostaglandin E. These results suggest that the effect of triamterene on renal prostaglandin E synthesis is different from that of spironolactone and that the change in urinary prostaglandin E after the administration of triamterene is not the reflection of the change in the renin-angiotensin-aldosterone system.

Adolescent↗
PubMed2005

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.

Adolescent↗
PubMed1988

Pharmacokinetic drug interactions between triamterene and ranitidine in humans: alterations in renal and hepatic clearances and gastrointestinal absorption.

Ranitidine reduces the renal tubular secretion of the organic cations procainamide and N-acetylprocainamide in humans through competition for transport via the organic cation transport system. Ranitidine is thought to spare phase I hepatic metabolism mediated by cytochrome P-450, unlike its counterpart H2-receptor antagonist cimetidine. The aim of the present study was to determine, in eight human subjects, the effect of ranitidine on the disposition of the potassium-sparing diuretic triamterene, which undergoes renal tubular secretion, hepatic hydroxylation and subsequent sulphate conjugation to a pharmacologically active metabolite. Multiple blood and urine samples were collected throughout a dosing interval after chronic administration of triamterene alone, ranitidine alone or the two in combination. Ranitidine significantly (P less than .05) reduced the renal clearances of triamterene (51%) and p-hydroxytriamterene sulphate conjugate (47%), the clearance by hydroxylation of triamterene (30%) and the apparent absorption of triamterene (52%). In turn, triamterene reduced the renal clearance of ranitidine (14%). The interaction resulted in a small attenuation of the pharmacodynamic response to triamterene. These results necessitate consideration of the underlying mechanisms of the interactions and fall outside of our present understanding of the renal clearance of sulphate conjugates and the metabolic inhibitory effects of ranitidine. Competition for translocation across membranes is postulated as a common mechanism for the observed renal and hepatic interactions.

Adult↗