Development of In Vitro-In Vivo Correlation for Potassium Chloride Extended Release Tablet Formulation Using Urinary Pharmacokinetic Data.

PURPOSE: To develop and validate a Level A in vitro-in vivo correlation (IVIVC) for potassium chloride extended-release (ER) formulations. METHODS: Three prototype ER formulations of potassium chloride with different in vitro release rates were developed and their urinary pharmacokinetic profiles were evaluated in healthy subjects. A mathematical model between in vitro dissolution and in vivo urinary excretion, a surrogate for measuring in vivo absorption, was developed using time-scale and time-shift parameters. The IVIVC model was then validated based on internal and external predictability. RESULTS: With the established IVIVC model, there was a good correlation between the observed fraction of dose excreted in urine and the time-scaled and time-shifted fraction of the drug dissolved, and between the in vitro dissolution time and the in vivo urinary excretion time for the ER formulations. The percent prediction error (%PE) on cumulative urinary excretion over the 24 h interval (Ae0-24h) and maximum urinary excretion rate (Rmax) was less than 15% for the individual formulations and less than 10% for the average of the two formulations used to develop the model. Further, the %PE values using external predictability were below 10%. CONCLUSIONS: A novel Level A IVIVC was successfully developed and validated for the new potassium chloride ER formulations using urinary pharmacokinetic data. This successful IVIVC may facilitate future development or manufacturing changes to the potassium chloride ER formulation.

Estimation of Daily Sodium and Potassium Excretion Using Spot Urine and 24-Hour Urine Samples in a Black Population (Benin).

The 24-hour urine collection method is considered the gold standard for the estimation of ingested potassium and sodium. Because of the impracticalities of collecting all urine over a 24-hour period, spot urine is often used for epidemiological investigations. This study aims to assess the agreement between spot urine and 24-hour urine measurements to determine sodium and potassium intake. A total of 402 participants aged 25 to 64 years were randomly selected in South Benin. Spot urine was taken during the second urination of the day. Twenty-four-hour urine was also collected. Samples (2-mL) were taken and then stored at -20°C. The analysis was carried out using potentiometric dosage. The agreement between spot urine and 24-hour urine measurements was established using Bland-Altman plots. A total of 354 results were analyzed. Daily sodium chloride and potassium chloride urinary excretion means were 10.2±4.9 g/24 h and 2.9±1.4 g/24 h, respectively. Estimated daily sodium chloride and potassium chloride means from the spot urine were 10.7±7.0 g/24 h and 3.9±2.1 g/24 h, respectively. Concordance coefficients were 0.61 at d=-0.5 g, (d±2SD=-11 g and 10.1 g) for sodium chloride and 0.61 at d=-1 g, (d±2SD=-3.8 g and 1.8 g) for potassium chloride. Spot urine method is acceptable for estimating 24-hour urinary sodium and potassium excretion to assess sodium and potassium intake in a black population. However, the confidence interval for the mean difference, which is too large, makes the sodium chloride results inadmissible at a clinical level.

Electrical conductivity measurements of urine as a new simplified method to evaluate the diuretic activity of medicinal plants.

ETHNOPHARMACOLOGICAL RELEVANCE: Diuretic plants are widely used in traditional medicine in many countries. However, many of these species have not been subjected to experimental studies to confirm that property. In this paper, a simple new method is proposed to evaluate the diuretic activity of plants. We define a new index that takes into account only the volume of urinary excretion and total ion concentration excreted obtained by specific electrical conductivity measurements. MATERIALS AND METHODS: Urine was collected in a graduate cylinder during the 8h after Artemisia thuscula (AT), Withania aristata (WA), Smilax canariensis (SC) and HCTZ oral administration to laboratory mice. To obtain the new index Diuretic Power (DP), we measured the specific electrical conductivity (κ) of the fresh urine samples. We calculated the concentration of a NaCl (or KCl) aqueous solution that has the same specific electrical conductivity as the urine sample. We multiplied this concentration by the corresponding urinary excretion volume, thus obtaining the total mEq. of electrolyte excreted "as if all were NaCl (or KCl)". Finally, we divided these mEq. by those corresponding to the control to obtain the DP value. RESULTS: HCTZ showed a 40% increase in DP, with respect to the control group, independently of the doses used, and the studied plants produced an increase between 7 and 28%. DP values were compared with other common indexes, DI and SIi, showing that the variation sequence of the three indexes was the same for HCTZ, WA and SC. CONCLUSIONS: A new and easy index, that we called diuretic power (DP), for estimating the diuretic activity of drugs or plants is proposed. It allows us to highlight diuretic effect with respect to a control value of a large amount of drugs or plants that had not been previously experimentally studied.

Effect of potassium salts in rats adapted to an acidogenic high-sulfur amino acid diet.

Low-grade metabolic acidosis, consecutive to excessive catabolism of sulfur amino acids and a high dietary Na:K ratio, is a common feature of Western food habits. This metabolic alteration may exert various adverse physiological effects, especially on bone, muscle and kidneys. To assess the actual effects of various K salts, a model of the Westernised diet has been developed in rats: slight protein excess (20 % casein); cations provided as non-alkalinising salts; high Na:K ratio. This diet resulted in acidic urine (pH 5.5) together with a high rate of divalent cation excretion in urine, especially Mg. Compared with controls, K supplementation as KCl accentuated Ca excretion, whereas potassium bicarbonate or malate reduced Mg and Ca excretion and alkalinised urine pH (up to 8). In parallel, citraturia was strongly increased, together with 2-ketoglutarate excretion, by potassium bicarbonate or malate in the diet. Basal sulfate excretion, in the range of 1 mmol/d, was slightly enhanced in rats fed the potassium malate diet. The present model of low-grade metabolic acidosis indicates that potassium malate may be as effective as KHCO3 to counteract urine acidification, to limit divalent cation excretion and to ensure high citrate concentration in urine.

In vitro and in vivo evaluation of potassium chloride sustained release formulation prepared with saturated polyglycolyed glycerides matrices.

The aim of the present work was to evaluate the effect of sustained release of potassium chloride semi-solid matrices prepared with different kinds and added amounts of Gelucires by the in vitro dissolution test and in vivo oral absorption study, and compared with a commercial product (slow-K). The results indicating that the release rates of potassium from experimental formulations were dependent on the type of semi-solid matrices (Gelucires). The higher the melting point of the Gelucires was incorporated, the slower release rate of the active substance was observed. Moreover, the values of similarity factor of Formulae F05 and F09 versus the reference in three kinds of dissolution medium (f(2)) were higher than 50, indicating that these experimental formulations had similar sustained release effects to the reference (slow-K) in dissolution test. In vivo study, the cumulative amount (mEq) of potassium excreted curve and the excretion rate curve of F05 and F09 were found to be similar to that of slow-K, and there were no significant differences (P > 0.05) in the maximum excretion rate and the mean time to reach the maximum rate between formulations and slow-K, indicating that the potassium chloride sustained release dosage form could be prepared using the Gelucires as lipid excipients.

The effect of potassium supplementation in persons with a high-normal blood pressure. Results from phase I of the Trials of Hypertension Prevention (TOHP). Trials of Hypertension Prevention (TOHP) Collaborative Research Group.

We conducted a randomized, double-blind, placebo-controlled trial of oral potassium chloride supplementation (60 mmol/d) in 353 men and women with an initial average diastolic blood pressure between 80 and 89 mm Hg. In the active (n = 178) compared to the placebo (n = 175) treatment group, the urinary potassium level was significantly (p < 0.001) increased by an average of 44.0 and 42.3 mmol/24 h following 3 and 6 months of therapy, respectively. Compared to placebo, active treatment was associated with a small (mean = 1.8 mm Hg) but significant (p = 0.04) reduction in diastolic blood pressure following 3 months of therapy. Following 6 months, however, this apparent treatment effect had virtually disappeared (mean reduction in diastolic blood pressure = 0.3 mm Hg). There was no significant effect of potassium supplementation on systolic blood pressure at either follow-up visit. There was a significant, independent, dose-response relationship between change in both 24-hour urinary potassium excretion and urinary sodium-potassium ratio and the corresponding change in diastolic blood pressure (-1.49 mm Hg for the highest versus the lowest quartile of change in urinary potassium excretion.

Crystalluria and urolithiasis in a relatively stone-free population.

The occurrence of renal stone in South African blacks is extremely rare. Whites however are prone to calculi to the same extent as that reported in other Western communities. The nature of the particulate material and crystalluria in urine samples from the two population groups were investigated using a Coulter Counter and scanning electron microscope. In addition, 10 calculi obtained from black patients over a 5 year period were analysed. The particle size distribution curves obtained for normal black and white males were identical. The curves for normal black and white females were also identical but different from those for males. Black male stone formers had larger particles than their controls while the single black female stone former investigated had particles of the same size as female controls, but in greater numbers. Scanning electron microscopy revealed profuse amounts of crystalline NaCl, KCl and other salts in the urinary sediments of blacks. These were not observed in the specimens from whites nor in the black stone formers' urines. Analysis of the calculi identified chemical and ultrastructural features similar to those observed in stones from whites. The hypothesis that the lower incidence of stone disease in blacks may be due to a high Na/Ca ratio is supported by our findings. It is suggested that various salts play a role in lowering the stone forming potential of such urines by a competitive substitution mechanism in which lattice calcium is displaced by sodium. It is also suggested that when urinary stone formation does occur in blacks, it does so via the same physicochemical mechanisms as in any other race group.

Hypophosphaturia impairs the renal defense against metabolic acidosis.

It is known that Pi normally provides the major source of non-NH3 urinary buffer and that Pi-buffered renal H+ excretion (titratable acidity, TA) accounts for a large fraction of daily renal net acid excretion (NAE). Whether the presence of luminal non-NH3 buffers is a prerequisite to normal renal regulation of systemic acid-base equilibrium under any conditions has not been investigated. Accordingly, I investigated whether chronic renal regulation of plasma (p) [HCO3] might be impaired under conditions of normophosphatemic hypophosphaturia (NHP) produced by short-term dietary Pi restriction. During a steady-state of HCl-induced acidosis in NaCl-replete NHP dogs (group 1A, N = 6), [HCO3-]p averaged 14.1 +/- 0.6 mEq/liter and arterial (a) [H+] averaged 54 +/- 2 nEq/liter. Substitution K+ 2.5 mEq/kg as neutral Pi for equivalent dietary KCl for 7 to 8 days resulted in significant amelioration of acidosis (delta [HCO3-]p + 2.2 +/- 0.5 mEq/liter, P less than 0.01; delta [H+]a -6 +/- 2 nEq/liter, P less than 0.01) in association with a cumulative increment (sigma delta) in TA excretion (+ 103 mEq, P less than 0.001) and NAE (+ 22 mEq). To investigate whether Pi-induced amelioration of acidosis was related to enhanced urinary buffer capacity, an additional group (group 1B, N = 5) with NHP and chronic HCl acidosis was administered the non-Pi buffer, neutral creatinine (5.0 mmoles/kg daily). As with Pi, acidosis was ameliorated by creatinine administration and sigma delta NAE increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium supplementation in ritodrine-induced hypokalemia.

Acute hypokalemia occurs during infusion of beta 2 agonists for tocolysis. This study examines the efficacy of supplemental potassium in treating this hypokalemia. Four groups of dogs were anesthetized and given lactated Ringer's solution (group I), potassium chloride (group II), ritodrine hydrochloride (group III), and ritodrine plus potassium (group IV). Arterial blood gases, pH, and serum and urinary electrolytes were measured. Results were analyzed by an analysis of variance. Serum potassium fell in groups I and III, rose in group II, and remained stable in group IV. Urinary potassium levels in groups that received ritodrine (III and IV) were not different from control levels. Potassium given with ritodrine will prevent hypokalemia. However, the risks of hyperkalemia exist if vigorous replacement is undertaken. There were no dysrhythmias and no adverse effects in any of the hypokalemic animals. Therefore, the routine administration of potassium is not advocated even in obstetric patients who undergo general anesthesia.

Low-sodium, high-potassium diet: feasibility and acceptability in a normotensive population.

Sixty-nine normotensive volunteers participated in an eight-week study to test the feasibility and acceptability of two low-sodium (less than 70 mEq), high-potassium (greater than 100 mEq) diets. The diet groups differed only in the use of KCl salt substitute. Both dietary groups were able to reduce sodium and increase potassium intake compared to the control group. Urine sodium excretion decreased in the diet groups but no change was observed in potassium. Potassium chloride salt substitute was not used as recommended, suggesting its unacceptability.

Overnight urine collections to estimate sodium intake.

This study was undertaken to formulate reliable confidence limits for the relationship between nocturnal and 24-hour urine sodium (Na) excretion for use in population compliance studies. Urine excretions were measured in 12 white and 12 black men at three levels of sodium (Na) intake (10, 200, and 400 mEq/day) for 7 days. Nocturnal Na, chloride (Cl), and Cl determined by titrator stick were all highly correlated (r greater than or equal to 0.86, p less than 0.001) with 24-hour UNaV. No significant difference could be attributed to race. Discriminate analysis revealed that the subjects could be categorized with respect to Na intake with accuracies of 95%, 90%, and 85% (low, middle, and high Na intake respectively) by means of two nocturnal urine Cl titrator stick measurements. In addition, two such measurements showing nocturnal UClV less than 10 mEq indicated with 95% accuracy that 24-hour UNaV was less than 60 mEq. According to these data, measurement of nocturnal Na or Cl excretion is a useful means of assessing compliance to a low sodium intake, and the titrator sticks are a convenient and inexpensive tool.

Impaired renal tubular potassium secretion in sickle cell disease.

We examined renal tubular function in six patients with sickle cell hemoglobin. All had normal inulin and para-aminohippurate clearances and impaired urinary concentrating and acidifying abilities. After intravenous potassium chloride administration, maximum excretion of potassium (U,V) was significantly lower in sickle cell patients than in control subjects, and the percentage of potassium load excreted in 5 h was markedly reduced. Urinary potassium excretion after sodium sulfate infusion was also markedly reduced in sickle cell patients compared to control subjects. After 40 mg of oral furosemide, U,V was also diminished in sickle cell patients. Plasma aldosterone response to ACTH and intravenous potassium was similar to that of control subjects. Plasma renin activity increased normally after volume contraction. We conclude that sickle cell patients have a defect in their ability to excrete an acute potassium load that cannot be attributed to abnormal renin or aldosterone secretion. Overall potassium homeostasis is maintained by extrarenal mechanisms during acute potassium loading.