Triamterene Increases Lithium Excretion in Healthy Subjects: Evidence for Lithium Transport in the Cortical Collecting Tubule

The possible presence of lithium transport beyond the proximaltubule was examined by measuring lithium excretion after administrationof triamterene, a potassium-sparing diuretic, exclusively actingin the cortical collecting tubule. Eight young and healthy volunteerswere studied on two occasions during maximal water diuresis.After obtaining baseline values triamterene (100mg orally) orplacebo was administered, and measurements continued for 4 hours.Creatinine clearance was used as a marker of glomerular filtrationrate, and phosphate excretion was used as an additional markerof proximal sodium transport. Compared to placebo (P), triamterene(T) caused a significant increase in fractional excretion ofsodium (P, 0.74±0.08%; T, 1.73±0.24%, mean±SEM;P<0.01), and lithium (P, 21.2±1.3%; T, 27.5±1.5%;P<0.01), whereas fractional excretion of phosphate remainedunchanged (P, 9.8±1.3%; T, 9.4±1.5%; P=NS). Theseresults indicate that lithium is transported in the corticalcollecting tubule, and provide further evidence that the useof lithium as a marker of purely proximal tubular sodium transportis of limited value.     

Blockade of epithelial Na+ channels by triamterenes — Underlying mechanisms and molecular basis

The three subunits (α, β, γ) encoding for the rat epithelial Na⁺ channel (rENaC) were expressed in Xenopus oocytes, and the induced Na⁺ conductance was tested for its sensitivity to various triamterene derivatives. Triamterene blocked rENaC in a voltage-dependent manner, and was 100-fold less potent than amiloride at pH 7.5. At −90 mV and −40 mV, the IC₅₀ values were 5 μM and 10 μM, respectively. The blockage by triamterene, which is a weak base with a pK _a of 6.2, was dependent on the extracellular pH. The IC₅₀ was 1 μM at pH 6.5 and only 17 μM at pH 8.5, suggesting that the protonated compound is more potent than the unprotonated one. According to a simple kinetic analysis, the apparent inhibition constants at −90 mV were 0.74 μM for the charged and 100.6 μM for the uncharged triamterene. The main metabolite of triamterene, p-hydroxytriamterene sulfuric acid ester, inhibited rENaC with an approximately twofold lower affinity. Derivatives of triamterene, in which the p-position of the phenylmoiety was substituted by acidic or basic residues, inhibited rENaC with IC₅₀ values in the range of 0.1–20 μM. Acidic and basic triamterenes produced a rENaC blockade with a similar voltage and pH dependence as the parent compound, suggesting that the pteridinemoiety of triamterene is responsible for that characteristic. Expression of the rENaC α-subunit-deletion mutant, Δ278–283, which lacks a putative amiloride-binding site, induced a Na⁺ channel with a greatly reduced affinity for both triamterene and amiloride. In summary, rENaC is a molecular target for triamterene that binds to its binding site within the electrical field, preferably as a positively charged molecule in a voltage- and pH-dependent fashion. We propose that amiloride and triamterene bind to rENaC using very similar mechanisms. Received: 2 January 1996/Accepted: 17 May 1996     

The interaction of triamterene at the myocardial beta receptor site

Triamterene (TA) inhibits in the microM range, as was previously shown in our laboratory, the positive inotropic action of beta-adrenoceptor agonists like isoproterenol in atrial preparations, when applied first. This interaction may be best explained by a direct influence of TA on the beta-adrenergic receptor-site itself or by an uncoupling of the signal transfer between receptor and adenylate cyclase complex at the inner sarcolemmal membrane site. For clarification we performed biochemical studies at freshly prepared membrane particles from guinea-pig hearts, combining both hypothetical sites of interaction. Binding studies with [3H]-dihydroalprenolol to the myocardial beta-adrenoceptor revealed that TA (1 to 10 mumol/l) did not disturb their functioning excluding a possible interaction at this membrane site. On the other hand we found a non competitive inhibition of the isoprenaline-activated adenylate cyclase while basic activity was not altered in the presence of triamterene (TA, 5 to 200 mumol/l). From the concentration-response curves a Ki-value of TA for half-maximal inhibition of 2.8 mumol/l was calculated. Since the sodium fluoride activated adenylate cyclase was also inhibited by triamterene in the same concentration range we conclude that it interferes with the signal-transfer between the beta-adrenoceptor site and the adenylate cyclase system through the plasmalemma.     

Direct determination of triamterene by potentiometry using a coated wire selective electrode

A coated wire triamterene-selective electrode based on the incorporation of a triamterene–tetraphenylborate ion-pair in a poly(vinylchloride) coating membrane was constructed. The influence of membrane composition, temperature, pH of the test solution, and foreign ions on the electrode performance were investigated. The electrode showed a Nernstian response over a triamterene concentration range from 1.0×10⁻⁶ to 3.5×10⁻² M, at 25 °C, and was found to be very selective, precise, and usable within the pH range 4.5–7.5. The standard electrode potentials, E°, were determined at 15, 20, 25, 30, 35, 40 and 45 °C and used to calculate the isothermal temperature coefficient (dE°/dt) of the electrode. Temperatures higher than 45 °C seriously affected the electrode performance. The electrode was successfully applied to the potentiometric determination of triamterene hydrochloride both in pure solutions and in pharmaceutical preparations.     

复方氨苯蝶啶的急性毒性及其保钾作用

目的：考察复方氨苯蝶啶的安全性及其保钾作用。方法：将NIH小鼠及SD大鼠分别用6%氨苯蝶啶、30%氢氯噻嗪和复方氨苯蝶啶混悬液灌胃,观察氨苯蝶啶、氢氯噻嗪及复方氨苯蝶啶的急性毒性及对尿钾的影响。结果：与氨苯蝶啶、氢氯噻嗪的急性毒性相比,复方氨苯蝶啶的急性毒性较低。氢氯噻嗪组排尿量和排钾量与对照组比较显著升高（P〈0.01）,氨苯蝶啶组排尿量增加不明显,但明显减少排钾（P〈0.01）;复方氨苯蝶啶组明显增加排尿量（P〈0.01）,排钾量略减少。结论：复方氨苯蝶啶的安全性好,氨苯蝶啶与氢氯噻嗪合用可增加利尿效应并预防低钾血症。     

Triamterene Suppresses Bombesin-enhanced Peritoneal Metastasis of Intestinal Adenocarcinomas Induced by Azoxymethane

The effects of combined administration of bombesin and the diuretic triamterene on the incidence of peritoneal metastasis of intestinal cancers induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM (7.4 mg/kg body weight) for 10 weeks and s.c. injections of bombesin (40 μg/kg body weight) every other day, and from week 16, s.c. injections of triamterene (10 and 20 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of both doses of triamterene with bombesin had little or no influence on the enhancement of intestinal carcinogenesis by bombesin, or the location, histologic type, depth of invasion, or labeling index of intestinal cancers, it significantly reduced the incidence of cancer metastasis. These findings indicate that triamterene suppresses cancer metastasis through a mechanism that does not affect the proliferation of intestinal cancers.     

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)     

Amiloride and the sodium channel

Summary Amiloride and the sodium channel. The diuretic drugs amiloride and triamterene have been used as probes for sodium channels in the mucosal surface of isolated frog skin. Both substances interact competitively with sodium for the channel. Using ¹⁴C-amiloride measurements were made of the number of channels present in the mucosal surface under a variety of conditions. The data suggests that a reliable estimate of sodium channel density can be made. Antidiuretic hormone applied to the serosal surface was found to have no effect on the numbers of channels, while the current passing through each channel was increased. The implications of these findings for the mechanism by which hormone alters the mucosal sodium permeability are discussed.     

Bioequivalence evaluation of a triamterene-hydrochlorothiazide generic product: a new bioequivalence index for fixed-dose combinations

In this study, an open, double-blind, randomized, two-period, two-group crossover design was conducted in 14 healthy volunteers to study the bioequivalence of a fixed-dose generic product. After administration of test or reference products to each volunteer, both active ingredients were determined simultaneously in plasma samples using a developed and validated HPLC-UV method, and pharmacokinetic parameters, including C(max), T(max), AUC(0-t) , AUC(0∞), terminal elimination rate constant (λz), volume of distribution in steady state (Vd(ss)), mean residence time (MRT), clearance (Cl), terminal elimination rate constant (Kel) were determined in each subject using the standard non-compartmental approach. Statistical comparison showed that the test and reference products were bioequivalent in terms of both the rate and extent of bioavailability of both active ingredients. Finally, a new parameter named range overlap index (ROI) was introduced for the first time in this study in order to judge about the overall bioequivalence of the combination products. This parameter indicates the extent in which the two CI90% ranges of each parameter for two active ingredients overlap with each other. The ROI is suggested to be equal or more than 50% for two combination products in order to be known as bioequivalent. The ROI values of the bioequivalence-indicating parameters were 61.90%, 84.6%, and 76.0% for C(max), AUC(0--->12), and AUC(0--->∞), respectively, which are indicative for bioequivalence in all the cases.