Cheryl D. Blume

Pharmacokinetic-pharmacodynamic analysis of unbound disopyramide directly measured in serial plasma samples in man.

The pharmacokinetics and pharmacodynamics of the antiarrhythmic drug, disopyramide, were investigated in 12 volunteers who took 300 mg doses of 3 different capsule preparations and an aqueous oral solution of the drug at 1-week intervals. Concentrations of drug unbound to plasma proteins were measured by a sensitive immunoenzyme assay after ultrafiltration of plasma samples taken serially after dosing. QT interval was measured on serial ECG recordings with correction for changes in heart rate. Unbound concentrations of disopyramide were modelled by an open one-compartment pharmacokinetic model with a zero-order absorption rate and a lag time. There was no significant difference in parameter estimates between the four preparations, except for the lag time, which was significantly shorter for the solution preparation. The saturable protein binding of disopyramide was described by a hyperbolic model including a specific binding site and additional nonspecific binding. The pharmacodynamic relationship between unbound drug concentration and QT prolongation was fit by a simple linear model. This fit was better using unbound concentration of the drug than using total concentrations.

Bioequivalence study of a new tablet formulation of triamterene and hydrochlorothiazide

A three-treatment, single-dose, crossover bioequivalence study was conducted in healthy volunteers to compare urinary drug recovery following administration of hydrochlorothiazide tablets, the currently marketed capsule formulation of triamterene and hydrochlorothiazide (Dyazide), and a new tablet preparation of these active ingredients (Maxzide). No significant differences were observed in the urinary recovery of hydrochlorothiazide after the administration of hydrochlorothiazide tablets and Maxzide tablets. However, only about one-half as much hydrochlorothiazide was recovered following the administration of Dyazide capsules. Similarly, the urinary recovery of triamterene and the sulfate ester of hydroxy-triamterene after administration of Dyazide capsules was approximately one-half the levels observed after giving the new tablet formulation. The clinical consequences of the limited bioavailability of the active ingredients of Dyazide are discussed.

Estrophilic molecules in the male guinea pig.

Abstract Following the intravenous administration of [ 3 H]-estradiol (300 μCi/kg) to mature male guinea pigs, the sex-accessory tissues (seminal vesicle muscle, seminal vesicle epithelium and prostate gland) and kidney incorporated greater concentrations of the native steroid than the liver, ileum, skeletal muscle or plasma. The seminal vesicle muscle was generally able to concentrate the greatest amount of [ 3 H]-estradiol. With a series of in vitro experiments, it was determined that these high concentrations of radioactivity associated with the sex-accessory tissues were not the result of active transport systems. However, it appears as if high affinity, steroid specific cytosolic estradiol binding molecules may serve as the intracellular determinants for the tissue selective distribution and retention of [ 3 H]-estradiol in vivo . Using Scatchard plot analyses, it was found that the seminal vesicle muscle possessed both the greatest concentration of estradiol binding sites and the highest equilibrium association constant. The cytosolic binding activities of the seminal vesicle epithelium, prostate gland and kidney were less than that of the seminal vesicle muscle but in great excess of the liver, skeletal muscle or plasma. These findings suggest that estradiol may potentially be a significant contributor to the function of sex-accessory tissue smooth muscle.

Effects of formulation and food on the absorption of hydrochlorothiazide and triamterene or amiloride from combination diuretic products.

The absorption of three combination formulations of hydrochlorothiazide and either triamterene or amiloride was studied over a 5-year period in seven separate investigations under varying conditions of food and fasting. The most widely prescribed combination, containing 25 mg of hydrochlorothiazide and 50 mg of triamterene, demonstrated impaired absorption in the fasting state that was partially corrected by the addition of a breakfast high in fat. The increase in the fat content of the food appeared to correlate directly with the amount of both drugs absorbed from this formulation. The second formulation studied, a new combination formulation of 50 mg of hydrochlorothiazide and 75 mg of triamterene, demonstrated acceptable absorption in the fasting state that was not altered by the concurrent administration of a high-fat breakfast. The absorption of the third formulation, a combination of 50 mg hydrochlorothiazide and 5 mg amiloride, was acceptable in the fasting state and demonstrated a slight reduction in the absorption of the amiloride component when administered concurrently with a high-fat meal. The clinical and biopharmaceutic implications of these observations are discussed.

A new antihypertensive agent: Maxzide (75 mg triamterene/50 mg hydrochlorothiazide)

The combination of potassium-sparing diuretics with hydrochlorothiazide is extensively used by hypertensive patients. In the United States, a capsule formulation containing 50 mg triamterene and 25 mg hydrochlorothiazide (Dyazide) is the most popular fixed-combination product. However, several investigators have confirmed that absorption of both the triamterene and hydrochlorothiazide components of Dyazide is markedly reduced. This reduced bioavailability may reduce its effectiveness in hypertensive patients who change from optimally bioavailable hydrochlorothiazide tablets to Dyazide capsules in an effort to correct hypokalemia. Scored tablets containing 75 mg triamterene/50 mg hydrochlorothiazide (Maxzide) have been developed using a patented parallel granulation manufacturing process and evaluated in a series of bioavailability-bioequivalence studies. The triamterene and hydrochlorothiazide components of Maxzide tablets were found to be as bioavailable as liquid preparations of the active ingredients given singly or in combination. Unlike Dyazide capsules, the hydrochlorothiazide component of Maxzide tablets was found to be absorbed to the same extent as single-entity hydrochlorothiazide tablets. These studies demonstrated that two Dyazide capsules (total of 100 mg triamterene/50 mg hydrochlorothiazide) deliver to the bloodstream approximately one-half the quantity of hydrochlorothiazide as one Maxzide (75 mg triamterene/50 mg hydrochlorothiazide) tablet or one 50 mg hydrochlorothiazide tablet. Similarly, two Dyazide capsules deliver approximately one-half the quantity of triamterene as one Maxzide tablet. The safety of Maxzide tablets (dose of one tablet a day) was then evaluated in three groups of hypertensive patients: those who previously had been given two Dyazide capsules a day, those who had received four Dyazide capsules a day, and newly diagnosed patients who had received no medication. The clinical condition of the patients who changed from two or four Dyazide capsules to one Maxzide tablet was not compromised. Indeed, significant reductions in blood pressures were observed, especially in some patients who had remained hypertensive while receiving Dyazide. As expected, the blood pressures of the previously untreated group also decreased significantly with Maxzide tablets. Clinically significant hyperkalemia or hypokalemia did not develop. There were no clinically significant changes in blood urea nitrogen, creatinine, or uric acid levels. In addition to enhanced bioavailability, Maxzide tablets offer the advantages of once-a-day dosing.

Clinical experience with a new combination formulation of triamterene and hydrochlorothiazide (Maxzide) in patients with mild to moderate hypertension

The results of an investigation to assess the clinical responses of patients with mild to moderate hypertension to a new combination formulation containing 75 mg triamterene and 50 mg hydrochlorothiazide are reported. One hundred fifty-six subjects entered the investigation. Subjects were divided into three groups, depending on whether they took two (group 1) or four capsules per day of a currently available formulation of triamterene and hydrochlorothiazide (Dyazide), or no antihypertensive medication prior to the start of the study. These medications were continued for an additional two weeks to generate baseline data. Thereafter, subjects received one tablet of the new combination formulation for four weeks. Seventy of the 156 participants received the new formulation for an additional period of at least 20 weeks. Observations during the study included sitting and standing pulse and blood pressure, weight, and serum electrolytes, uric acid, creatinine, and blood urea nitrogen levels. The results of the investigation indicated that subjects transferred to the new combination drug maintained normal serum electrolyte values, including potassium, with no or minor changes in the levels of uric acid, creatinine, and blood urea nitrogen. Reductions in systolic and diastolic blood pressure were observed in all three study groups, including subjects receiving two or four capsules of Dyazide per day in the two-week baseline period. We conclude that mild to moderately hypertensive subjects taking no medication or either two or four capsules of Dyazide per day may be transferred safely to the new combination product of triamterene and hydrochlothiazide.

Absence of a significant pharmacokinetic interaction between hydrochlorothiazide and triamterene when coadministered

Hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate were monitored in the plasma and urine of 24 healthy young men taking single doses of a liquid preparation containing both hydrochlorothiazide and triameterene, liquid preparations containing either of these drugs alone, and a combination tablet recently formulated with a dose ratio of hydrochlorothiazide: triamterene (1∶1,5) found to give optimal potassium-sparing effect. In contradiction to a recent publication, no interaction between the drugs affecting the bioavailability or renal clearance of either could be demonstrated. The previous report of drug-drug interaction probably arose from formulationrelated problems with bioavailability from the two capsule and two tablet products which had been studied. A well-formulated hydrochlorothiazide-triamterene combination tablet promotes plasma concentrations and urinary excretion of hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate which are virtually identical to those seen after either a combination liquid dosage form or simple liquid forms containing only one of the two drugs.

Absorption and disposition of two combination formulations of hydrochlorothiazide and triamterene: Influence of age and renal function

In this study we compared the absorption and disposition of two commonly used combination formulations of hydrochlorothiazide and triamterene (Dyazide and Maxzide) in 48 patients with essential hypertension after dosing with each formulation to steady state. Interdose AUC and urinary recovery of hydrochlorothiazide, triamterene, and the major metabolite of triamterene, hydroxytriamterene sulfate (adjusted for dose), documented marked impairment in the absorption of hydrochlorothiazide (approximately two third as bioavailable) and triamterene (about half as bioavailable) from Dyazide in comparison to Maxzide. The study also demonstrated a reduction in the clearance of triamterene, hydrochlorothiazide, and hydroxytriamterene sulfate with increasing age. Linear correlation analyses suggested that this effect was a result of the reduction in renal function that occurs with increasing age.