Triamterene is cytotoxic to HCT116 and CT26 cells, with IC50 values of 31.30 and 24.45 μM [5]. Triamterene (100 and 200 µM, 2 hours) promotes lysosomal rupture, lowers lysosomal integrity, and triggers lysis in HepG2 cells [6]. Triamterene (10-100 µM) suppresses delayed rectifier potassium currents in guinea pig ventricular myocytes [7].

In addition to intravenous pentylenetetrazole (PTZ) (0.5%, 1 mL/min), intraperitoneal PTZ (85 mg/kg), and maximal shock seizures (shown anticonvulsant efficacy in a rat model of MES)-induced convulsions, trimeterene (10–40 mg/kg/day PO, 5 days) is administered [3]. In awake saline rats, triamterene (25 mg/kg) lowers urine magnesium excretion [4].

Immunofluorescence[6]
Cell Types: HepG2 cells
Tested Concentrations: 100 and 200 µM
Incubation Duration: 2 h
Experimental Results: Induced Gal3-puncta formation. Induced the translocation of TFEB to the nucleus from the cytosol.

Absorption, Distribution and Excretion
Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents.
Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide.
In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals.
The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers.
Earlier in vivo studies revealed a low concentration of triamterene in the brain of guinea pigs and baboons, and a transfer of the drug from the fetus to the mother. Additional investigations have been performed to characterize further the transport system(s) for triamterene in the central nervous system (CNS), placenta, and kidney. In guinea pigs a very low brain to free plasma concentration ratio (0.1) was achieved 3.5 min after drug administration and was maintained during 180 min of drug infusion. The cerebrospinal fluid (CSF) concentration was similar to the concentration of the drug in the brain. A higher brain to free plasma concentration ratio was gradually reached in dogs studied with nanogram per ml and microgram per ml concentrations of triamterene in CSF. Administration of triamterene to fetal and maternal sheep revealed a placental extraction (E) from fetal plasma to placenta 20 times greater than that from maternal plasma to placenta. The E from fetal plasma to placenta was unaffected by a triamterene concentration in the maternal circulation 10 times that in the fetus. These findings and studies of renal clearance support an active transfer of triamterene by the CNS, placenta, and kidney; the physiologic substrate for these systems is unknown.
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 hr 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. ...
Although renal elimination is only a minor route of excretion for triamterene, it is the main route of elimination of 4'-hydroxytriamterene sulfate. Thus, in individuals with renal impairment, accumulation of the sulfate is substantial and progressive, but negligible for triamterene. The kinetics of triamterene were observed in 32 patients with widely varying degrees of creatinine clearance (10-135 mL/minute), an indicator of renal function. In patients with reduced renal function, significant accumulation in plasma and reduced renal clearance of the sulfate were reported. Plasma concentrations of the parent drug were not increased.
Patients with liver cirrhosis have reduced ability to hydroxylate triamterene, as evidenced by high plasma concentrations of triamterene and low concentrations of 4'-hydroxytriamterene sulfate. After administration of 200 mg of triamterene, peak plasma concentrations in eight patients without liver disease were 559 +/- 48 ng/mL and 2956 +/- 320 ng/mL for triamterene and 4'-hydroxytriamterene sulfate, respectively. In the seven patients with alcoholic cirrhosis, peak plasma concentrations of triamterene were increased to 1434 +/- 184 ng/mL, while the concentrations of the sulfate were reduced to 469 +/- 84 ng/mL. Renal clearance was also reduced in patients with cirrhosis: the clearance of triamterene and the sulfate were 2.8 +/- 0.7 and 38.0 +/- 6.6 mL/minute, respectively, compared with 14.4 +/- 1.5 and 116.7 +/- 11.6 mL/ minute, respectively, in patients without liver disease.
For more Absorption, Distribution and Excretion (Complete) data for Triamterene (12 total), please visit the HSDB record page.

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Metabolism / Metabolites
Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma.
The metabolic and excretory fate of triamterene has not been fully determined. The drug is reportedly metabolized to 6-p-hydroxytriamterene and its sulfate conjugate.
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 hr 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. ...
Patients with liver cirrhosis have reduced ability to hydroxylate triamterene, as evidenced by high plasma concentrations of triamterene and low concentrations of 4'-hydroxytriamterene sulfate. After administration of 200 mg of triamterene, peak plasma concentrations in eight patients without liver disease were 559 +/- 48 ng/mL and 2956 +/- 320 ng/mL for triamterene and 4'-hydroxytriamterene sulfate, respectively. In the seven patients with alcoholic cirrhosis, peak plasma concentrations of triamterene were increased to 1434 +/- 184 ng/mL, while the concentrations of the sulfate were reduced to 469 +/- 84 ng/mL. Renal clearance was also reduced in patients with cirrhosis: the clearance of triamterene and the sulfate were 2.8 +/- 0.7 and 38.0 +/- 6.6 mL/minute, respectively, compared with 14.4 +/- 1.5 and 116.7 +/- 11.6 mL/ minute, respectively, in patients without liver disease.

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Biological Half-Life
The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug.
The plasma half-life of triamterene is 100-150 minutes.

Toxicity Summary
IDENTIFICATION AND USE: Triamterene is epithelial sodium channel blocker, which is used as diuretic in human patients, as well as in veterinary medicine in dogs and cats. There is little experience associated with its use in dogs or cats and it is rarely recommended. HUMAN STUDIES: Overdosage of triamterene may cause electrolyte imbalance, especially hyperkalemia. Nausea, vomiting, other GI disturbances, and weakness may also occur. Hypotension may also result, especially when the drug is used concomitantly with hydrochlorothiazide or other diuretics or hypotensive agents. Mucosal ulceration and severe bone-marrow insufficiency with marked megaloblastic transformation occurred during treatment with triamterene in a patient with decompensated alcoholic liver cirrhosis and malnutrition. Two cases of triamterene crystalline nephropathy have been reported. Acute intravascular hemolysis and renal failure developed while a patient was taking triamterene. ANIMAL STUDIES: In the first study in mice, triamterene caused significant increases in the incidences of hepatocellular adenoma in females. In a second study, survival of exposed mice was similar to that of controls. There were significant increases in the incidence of hepatocellular adenoma in males and females, and of hepatocellular adenoma or carcinoma (combined) in females. The incidence of liver foci was increased in some groups of treated mice in both the first and second studies. Treatment with triamterene also caused treatment-related thyroid follicular cell hyperplasia. Triamterene caused a significant increase in the incidence of hepatocellular adenoma in male rats. Hepatocellular adenoma was present in all three dosed groups of males and not in males in the control group. There was no significant increase in the incidence of tumors in female rats. Reproduction studies have been performed in rats without evidence of harm to the fetus due to triamterene. Triamterene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary cells, with or without metabolic activation. Positive results were obtained for induction of sister chromatid exchanges in Chinese hamster ovary cells with and without metabolic activation.

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Hepatotoxicity
Triamterene therapy has been associated with rare instances of idiosyncratic, clinically apparent liver injury which have invariably been mild and anicteric. The liver injury typically arises after 4 to 12 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular or mixed. Fever is a prominent symptom and the reaction is often more typical of drug-fever than hepatotoxicity (Case 1). Rash and eosinophilia can occur, but are usually not prominent. Autoantibodies are rare. All published cases of triamterene associated liver injury have been self-limited in course and resolved rapidly upon withdrawal.
Likelihood score: D (possible rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because there is no published experience with triamterene during breastfeeding, other agents may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Intense diuresis can suppress lactation; however, it is unlikely that triamterene alone is sufficiently potent to cause this effect.

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Protein Binding
67% bound to proteins.

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Interactions
Oral bioavailability of hydrochlorothiazide from the original formulation (no longer commercially available) of Dyazide capsules was about 50-65% that from Maxzide tablets or single-entity tablets or solutions of the drug. In one crossover study in a limited number of healthy adults receiving single doses of the drug, the mean hydrochlorothiazide dose recovered in urine within 72 hours was about 30% for the original formulation of Dyazide capsules and about 60% for Maxzide or single-entity tablets of the drug. In 1995, Dyazide capsules were reformulated to improve the oral bioavailability of triamterene and hydrochlorothiazide. The oral bioavailabilities of triamterene and hydrochlorothiazide from the reformulated Dyazide capsules now are comparable to those of aqueous suspensions of the individual drugs, averaging 85 and 82%, respectively, for the new formulation and 100 and 100%, respectively, for the suspensions. In addition, intraindividual variation in bioavailability from the reformulated Dyazide capsules was reduced by about 40% compared with the original formulation. The manufacturer states that the reformulated Dyazide capsules also are bioequivalent to single-entity 25-mg hydrochlorothiazide tablets and 37.5-mg triamterene capsules. Administration of reformulated Dyazide with a high-fat meal in healthy adults increased the average bioavailabilities of triamterene by about 67%, 6-p-hydroxytriamterene by about 50%, and hydrochlorothiazide by about 17% and the peak concentrations of triamterene and its p-hydroxy metabolite and delayed the absorption of the active drugs by up to 2 hours.
Triamterene should not be used concurrently with another potassium-sparing agent (e.g., amiloride, spironolactone), since concomitant therapy with these drugs may increase the risk of hyperkalemia compared with triamterene alone. At least 2 deaths have been reported in patients receiving triamterene and spironolactone concurrently; in one patient, recommended dosages were exceeded and, in the other patient, serum electrolytes were not closely monitored. Potassium-sparing diuretics should be used with caution and serum potassium should be determined frequently in patients receiving an angiotensin-converting enzyme (ACE) inhibitor (e.g., captopril, enalapril), since concomitant administration with an ACE inhibitor may increase the risk of hyperkalemia. Dosage of triamterene should be reduced or the drug should be discontinued as necessary. Patients with renal impairment may be at increased risk of hyperkalemia.
In a three-way crossover study, 23 patients with hepatic cirrhosis, ascites, and dependent edema received 40 mg/day of furosemide alone and combined with triamterene 50 mg/day and triamterine 100 mg/day. Baseline potassium excretion did not increase when furosemide was given alone, but potassium excretion fell when 50 mg or 100 mg of triamterene was also given. Both doses of triamterene augmented the natriuretic effect of furosemide.
Concurrent administration of triamterene with potassium supplements, potassium-containing medications (e.g., parenteral penicillin G potassium), or other substances containing potassium (e.g., salt substitutes, low-salt milk) may increase the risk of hyperkalemia as compared with triamterene alone, and such combined use is contraindicated.
For more Interactions (Complete) data for Triamterene (11 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 400 mg/kg
LD50 Rat ip 200 mg/kg
LD50 Mouse oral 285 mg/kg
LD50 Mouse ip 249 mg/kg
LD50 Mouse sc 620 mg/kg

[1]. Blockade of epithelial Na+ channels by triamterenes - underlying mechanisms and molecular basis. Pflugers Arch, 1996. 432(5): p. 760-6.

[2]. Pharmacokinetics of triamterene after i.v. administration to man: determination of bioavailability. Eur J Clin Pharmacol, 1983. 25(2): p. 237-41.

[3]. A role for ATP-sensitive potassium channels in the anticonvulsant effects of triamterene in mice. Epilepsy Res. 2016 Mar;121:8-13.

[4]. The effects of amiloride and triamterene on urinary magnesium excretion in conscious saline-loaded rats. Br J Pharmacol. 1981 Feb;72(2):285-9.

[5]. In vitro cytotoxicity and DNA/HSA interaction study of triamterene using molecular modelling and multi-spectroscopic methods. J Biomol Struct Dyn. 2019 Jun;37(9):2242-2253.

[6]. Triamterene induces autophagic degradation of lysosome by exacerbating lysosomal integrity. Arch Pharm Res. 2021 Jun;44(6):621-631.

[7]. Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes. Circ Res. 1994 Jun;74(6):1114-20.

Therapeutic Uses
Diuretics; Epithelial Sodium Channel Blockers
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Triamterene is included in the database.
Dyrenium (triamterene) is indicated in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism. /Included in US product labeling/
Dyrenium may be used alone or with other diuretics, either for its added diuretic effect or its potassium-sparing potential. It also promotes increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for Triamterene (6 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ Warnings: Abnormal elevation of serum potassium levels (greater than or equal to 5.5 mEq/liter) can occur with all potassium-sparing agents, including Dyrenium. Hyperkalemia is more likely to occur in patients with renal impairment and diabetes (even without evidence of renal impairment), and in the elderly or severely ill. Since uncorrected hyperkalemia may be fatal, serum potassium levels must be monitored at frequent intervals especially in patients receiving Dyrenium, when dosages are changed or with any illness that may influence renal function.
Dyrenium should not be given to patients receiving other potassium-sparing agents, such as spironolactone, amiloride hydrochloride, or other formulations containing triamterene. Two deaths have been reported in patients receiving concomitant spironolactone and Dyrenium or Dyazide. Although dosage recommendations were exceeded in one case and in the other serum electrolytes were not properly monitored, these two drugs should not be given concomitantly.
Dyrenium (triamterene) should not be used in patients with pre-existing elevated serum potassium, as is sometimes seen in patients with impaired renal function or azotemia, or in patients who develop hyperkalemia while on the drug. Patients should not be placed on dietary potassium supplements, potassium salts or potassium-containing salt substitutes in conjunction with Dyrenium.
Potassium loss has been reported during triamterene therapy in some patients with hepatic cirrhosis and may result in signs and symptoms of hepatic coma or precoma. Serum potassium concentrations should be closely monitored in patients with hepatic cirrhosis and potassium supplementation administered if required.
For more Drug Warnings (Complete) data for Triamterene (25 total), please visit the HSDB record page.

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Pharmacodynamics
Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide.

C12H11N7

253.26

253.108

396-01-0

Triamterene (Standard);396-01-0;Triamterene-d5;1189922-23-3

5546

Light yellow to yellow solid powder

1.502 g/cm3

573.4ºC at 760 mmHg

316°C

11 °C

2.577

3

7

1

19

307

0

FNYLWPVRPXGIIP-UHFFFAOYSA-N

InChI=1S/C12H11N7/c13-9-7(6-4-2-1-3-5-6)16-8-10(14)18-12(15)19-11(8)17-9/h1-5H,(H6,13,14,15,17,18,19)

6-phenylpteridine-2,4,7-triamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 1.67 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 1.67 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5%CMC Na +1% Tween 80: 30mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)