Changes in serum potassium levels occurring in patients treated with triamterene and a triamterene‐hydrochlorothiazide combination

Hansen, Karl B.; Bender, A. Douglas

doi:10.1002/cpt196783392

Cited by 32 publications

(8 citation statements)

References 10 publications

(11 reference statements)

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“…Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide. 10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity.…”

Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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In recent years, cucurbit [7]uril (CB [7]) has attracted great attention in drug delivery. Though the effect of CB [7] in enhancing the solubility of water insoluble drugs has been validated, the underlying mechanism remains poorly understood, particularly at a molecular level. This study is designed to evaluate a CB [7]-based pharmaceutical formulation to improve solubility and bioavailability of triamterene (a mild potassium-sparing diuretic). Two polymorphs of triamterene@CB [7] were obtained, and their crystal structures were determined by single crystal X-ray diffraction. The CB [7] molecule forms a stable host−guest complex with triamterene (K a = 1.69 ± 0.34 × 10 4 M −1 ) in aqueous solution (pH = 1.0). The results of dissolution study demonstrate that the apparent solubility value of triamterene@CB [7] complex in 0.1 M HCl is 1.6 times as large as that of triamterene, while free triamterene was released from triamterene@CB [7] complex in phosphate buffer of pH 6.8. Pharmacokinetic studies in rats reveal that the AUC 0−∞ value of triamterene@CB [7] complex increases 2.8-fold compared with that of free triamterene, and t 1/2 is prolonged from 1.42 to 2.61 h (P < 0.05) after oral administration. The increased solubility and oral bioavailability are attributed to the formation of a hydrophilic capsule composed of two CB [7] molecules, in which two insoluble triamterene molecules are encapsulated. These results demonstrate that triamterene@CB [7] complex is a stable and effective pharmaceutical formulation. KEYWORDS: cucurbit [7]uril, triamterene, crystal structure, solubility, pharmacokinetics ■ INTRODUCTIONPoor aqueous solubility is a major bottleneck in drug discovery and drug development: more than 40% of drug candidates are poorly water-soluble, and poor aqueous solubility is the main factor to restrict the bioavailability of drugs.1,2 Various approaches have been investigated to improve solubility of drugs, including cocrystal, 3,4 salts, 5 prodrugs, 6 solid dispersion, 7 macrocyclic hosts (e.g., cyclodextrins, cucurbiturils), 8,9 etc. Triamterene, 2,4,7-triamino-6-phenylpteridine (Scheme 1) is a mild potassium-sparing diuretic used either alone or in combination with potassium-wasting diuretics such as hydrochlorothiazide.10,11 It displays low oral bioavailability, and there exists wide intersubject variation because of its poor aqueous solubility (45 mg/L). 12,13 Though triamterene contains three primary amine groups, various methods to obtain soluble salts failed, probably due to its weak basicity. 12 To date, only a few formulations have been proposed to improve the solubility of triamterene, including cyclodextrins 14,15 and solid dispersions. 16,17 However, parenteral administration of β-cyclodextrin results in renal toxicity, 18 and solid dispersions are often physically unstable upon storage at elevated temperature and humidity, 19 and neither of the two triamterene formulations has been applied for clinical therapy. Therefore, the development of new pharmaceutical formulation of triam...

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Section: ■ Introductionmentioning

confidence: 99%

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Chen

Jiang

et al. 2013

Mol. Pharmaceutics

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“…A reduction in hyperkalemia would be expected from treatment with a combination of spironolactone with diuretics (3, 6, 9, 13, 17, 18). Spironolactone inhibits potassium loss (8) and diuretics inhibit potassium retention (13, 17). Therefore, it was surprising that hyperkalemia was observed more frequently in Groups B and C receiving combined treatment than in Group A treated with spironolactone alone.…”

Section: Discussionmentioning

confidence: 99%

Hyperkalemic Changes During Spironolactone Therapy for Cirrhosis and Ascites, With Special Reference to Hyperkalemic Intermittent Paralysis

Marosi

Szende

et al. 1968

J American Geriatrics Society

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The frequency and clinical significance of the hyperkalemia associated with spironolactone therapy was studied by analyzing 755 serum potassium values obtained on 29 patients with cirrhosis and ascites. The patients were classified as follows:I) control group treated intermittently with combinations of conventional diuretics; and 2) spironolactone groups-(A) patients treated with spironolactone alone, and (B and C) nonazotemic and slightly azotemic patients, respectively, treated with spironolactone plus diuretics.Hyperkalemia was indicated in 3.3 per cent of 302 control serum potassium determinations, and in 48 per cent of 325 determinations made during spironolactone treatment. The increase in serum potassium concentration was more marked in the slightly azotemic group, although the initial levels were no higher than in the other groups of patients. Hyperkalemic intermittent paralysis associated with spironolactone therapy occurred in 5 patients. Studies of the urinary excretory patterns suggested a distal as well as a proximal tubular site of action of spironolactone. The significance of the tubular levels of spironolactone action in the development of hyperkalemia is discussed.

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“…TA has been utilized either alone [18,19] or in combi nation with potassium-wasting diuretics, such as thia zides [4,[20][21][22] or furosemide [23,24], to both increase natriuresis as well as to minimize the ensuing kaliuresis. TA inhibits passive sodium transport from the luminal side of transporting epithelia [25][26][27], resulting in im paired movement of potassium from cell to lumen, since the latter is functionally coupled to sodium movement.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

“…It has been commonly employed in combination with more potent diuretics in order to minimize their propensity to induce kaliuresis [2][3][4], A popular combination in this regard is Dyazide which contains 50 mg of TA and 25 mg of hydrochlorothiazide (HCT).…”

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confidence: 99%

Triamterene and the Kidney

Sica¹,

Gehr²

1989

Nephron

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Triamterene (TA) is a mild ‘potassium-sparing’ diuretic usually employed in combination with other more potent diuretics in the treatment of hypertension. TA pharmacokinetics and pharmacodynamics in normal volunteers, elderly subjects and in patients with renal and hepatic dysfunction are reviewed. A variety of adverse renal effects, such as abnormalities in urinary sediment, nephrolithiasis, interstitial nephritis and acute renal failure, has been reported to occur and is also reviewed. Of particular concern with the increased availability of ‘over-the-counter’ nonsteroidal anti-inflammatory medications (NSAID) is the adverse interaction between TA and NSAID which may culminate in acute renal failure. Although a rare occurrence, the clinician should be aware of potential adverse reactions associated with the use of TA.

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Changes in serum potassium levels occurring in patients treated with triamterene and a triamterene‐hydrochlorothiazide combination

Cited by 32 publications

References 10 publications

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

The Delivery of Triamterene by Cucurbit[7]uril: Synthesis, Structures and Pharmacokinetics Study

Hyperkalemic Changes During Spironolactone Therapy for Cirrhosis and Ascites, With Special Reference to Hyperkalemic Intermittent Paralysis

Triamterene and the Kidney

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