Pharmacokinetics and steady-state myocardial uptake of disopyramide in the dog.

The pharmacokinetics and steady-state myocardial uptake of the antiarrhythmic drug disopyramide (DP) were determined in dogs after oral or intravenous administration of [14C]disopyramide phosphate. DP was absorbed rapidly and its absolute oral bioavailability was about 70%. Significant dose-dependent kinetics were not apparent after 7.5- to 30-mg/kg po doses. Plasma half-lives of DP were about 2.9 and 1.2 hr after the po and iv doses, respectively. DP and its N-dealkylated metabolites were largely excreted in the urine and their composition was qualitatively similar after the po and iv doses. Marked differences in the protein binding of DP in human and dog plasma were found. In the papillary muscle, ventricular septum, and ventricles of one dog, the steady-state concentrations of DP and its less active mono-N-dealkylated metabolite were about twice those in plasma, whereas in the atria and tricuspid and mitral valves they were similar to those in plasma.

Species differences in the metabolism and disposition of spironolactone.

The absorption, excretion and metabolism of [22-14C]spironolactone was compared in Charles River rats, beagle dogs and rhesus monkeys. The drug was administered at the fixed dose of 5 mg/kg po and iv. From the po/iv ratios of the areas under the plasma radioactivity-time curves, the gastrointestinal absorption of the drug was estimated to be 82% in the rat, 62% in the dog, and 103% in the monkey. The absolute bioavailability of a pharmacologically active metabolite, canrenone, was 57% in the dog and 48% in the monkey. Spironolactone was extensively metabolized in all three species and differences existed in the composition of the metabolites in their plasma, urine, and feces. The amount of radioactivity that was excreted in the urine and feces of all three species was similar after either po or iv administration of the drug. The cumulative average excretion of radioactivity in the urine as percentage of the po dose in 6 days was 4.69% in the rat (N = 5), 18.5% in the dog (N = 3), and 46.0% in the monkey (N = 3). In the feces, the corresponding excretion values were 74.2, 69.3 and 40.1%, respectively. Canrenone excretion in the urine constituted 0.65% of the po dose in the rat, 0.82% in the dog, and 5.86% in the monkey, whereas the excretion of total fluorogenic metabolites constituted 1.1, 1.9, and 12.1% respectively. Comparison of animal data with those published for humans indicated that the disposition and metabolism of spironolactone in the rhesus monkey, rather than those in the rat or the dog, was closest to that in man.

In vitro and in vivo availability of spironolactone from oral dosage forms.

Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.

Spironolactone. I. Disposition and metabolism.

This study describes absorption, excretion, and metabolism of[20(-3)H]-spironolactone (SP) in 5 healthy men. After a single oral dose (200 mg + 200 muCi) of the drug given in alcoholic solution, the peak serum levels of the ethyl acetate-extractable tritium and the dethioacetylated metabolite canrenone were 763 +/- 400 ng/ml (mean +/- SD) and 415 +/- 145 ng/ml, respectively. These levels occurred within 3 hr. The serum half-life (T1/2) of the extractable materials was 37.3 +/- 6.53 hr. Canrenone levels declined in two phases. The T1/2 from 2.5 to 12 hr was 4.42 +/- 1.07 hr and from 12 to 72 hr was 16.8 +/- 2.75 hr. In the blood both SP and canrenone were confined largely in the plasma, and their protein binding exceeded 89% at concentrations of 550 and 710 ng/ml, respectively. In 5 days 31.6 +/- 5.87% of the radioactivity was excreted in the urine and 22.7 +/- 14.1% in the feces. Unchanged SP was not detected in the urine. The major urinary metabolites were canrenone (5.04 +/- 2.83% of dose), 6beta-OH-sulfoxide (5.21 +/- 0.93% of dose), and canrenoate ester glucuronide (6.2% of dose).

Spironolactone. II. Bioavailability.

The bioavailability of commercial 25-mg spironolactone tablets and a new tablet preparation containing 100 mg of the drug has been determined in 12 healthy male subjects. After a 200-mg oral dose of the drug given in a solution of polyethylene glycol-400, the peak plasma level of the dethioacetylated metabolite canrenone was 633 +/- 154 ng/ml (mean +/- SD) and was reached at 1.4 +/- 0.43 hr. This peak was higher and was achieved earlier than after either eight 25-mg tablets (480 +/- 155 ng/ml at 2.9 +/- 1.03 hr) or two 100-mg tablets (474 +/- 182 ng/ml at 3.0 +/- 1.37 hr). From the ratio of the 24-hr area under the plasma concentration-time curves, the bioavailabilities of the two tablet preparations relative to the solution were 99.6 +/- 18.2% and 92.1 +/- 22.9%, respectively. The amount of canrenone excreted in the urine by 48 hr was 4.48 +/- 1.26 mg (solution), 6.36 +/- 2.02 mg (eight 25-mg tablets), and 7.81 +/- 1.87 mg (two 100-mg tablets), representing 2% to 4% of the administered dose. It is concluded that urinary excretion of canrenone alone is not a reliable method for determining the bioavailability of spironolactone.

Spironolactone. III. Canrenone--maximum and minimum steady-state plasma levels.

Steady-state plasma levels of canrenone have been examined in 23 healthy men who received repeated doses of spironolactone for 15 days. The dose regimens were 200 mg once a day and 50 mg 4 times a day. With both treatments the steady-state levels were reached after 3 to 4 days. With once-a-day treatment, the maximum and minimum steady-state levels were about 500 and 100 ng/ml, respectively. The minimum levels with treatment 4 times a day were about 200 ng/ml. The post steady-state half-life of canrenone with once-a-day treatment (19.2 +/- 6.57 hr) was longer (p less than 0.01) than the half-life obtained in the 4 times-a-day treatment (12.5 +/- 3.39 hr). The former half-life was similar to the log-linear phase half-life of canrenone in the single-dose studies.