Lack of effect of bilateral nephrectomy on the pharmacokinetics of 14C-indapamide (REV 2555) and its metabolites in the dog.

Renal impairment can affect the disposition of metabolites, as well as unchanged drug, especially when there is significant renal clearance of metabolites. The pharmacokinetics of indapamide, a highly metabolized drug, and total indapamide equivalents (as an indicator of metabolites plus unchanged drug) were determined in the anephric dog. An intravenous dose of 14C-indapamide was administered to dogs first after a sham-operation, and then following bilateral nephrectomy. The disposition of total indapamide equivalents, calculated from total radioactivity, was not substantially different after nephrectomy as compared to after sham-operation, with an increase after nephrectomy in the area under the blood level curve (+26.2%), and decreases in the elimination rate constant (-6.9%), volume of distribution (-12.7%) and total blood clearance (-21.9%). The only statistically significant change was the decrease in the volume of distribution. The elimination kinetics of unchanged drug were also qualitatively similar in both cases. After nephrectomy, a decrease was seen in the elimination rate constant (-10.9%) and the volume of distribution (-16.3%) while slight increases in the total blood clearance (+1.9%) and the area under the blood level curve (+4.8%) were noted. These findings could have important implications for advantageous use of indapamide in treatment of hypertensive patients with renal failure since these data suggest that metabolites as well as unchanged drug could still be effectively eliminated by an alternate, non-renal route, thus minimizing accumulation of these compounds.

Pharmacokinetics and bioavailability of indapamide--a new antihypertensive drug.

Two formulations of indapamide tablets (2.5 mg) were given as a 5.0 mg dose and the subsequent blood levels were compared to those obtained after administration of a 5.0 mg solution. The study was conducted as a randomized three-way crossover design using healthy male volunteers. The drug was well tolerated by all the subjects involved. The area under the blood concentration versus time curve, extrapolated to infinity was essentially the same for all three formulations (4.2, 4.7, and 4.4 microgram-h/ml). Statistical comparison of the blood levels from the two tablets showed that one tablet had a significantly shorter time of maximum blood concentration (2.3 vs 3.5). Cmax(333ng/ml) and tmax (0.7h) values for the solution were significantly higher than either tablet. The average half-life (beta-phase) for all three formulations was 15 h, while the average systemic clearance was 20 ml/min. Indapamide has a low clearance rate and there was no evidence that the drug undergoes a first-pass effect.

Pharmacokinetics of indapamide in dogs.

Four beagle dogs received both an oral and intravenous dose (1 mg/kg) of indapamide in a crossover design. The blood levels and urinary excretion of intact indapamide were measured, and the pharmacokinetic parameters of the drug were defined. The results indicate that indapamide is completely bioavailable after an oral dose and does not undergo first-pass metabolism. Excretion of unchanged drug from the kidney accounted for only a small percentage of the drug's clearance. While the dog is very similar to the human in its handling of indapamide, the dogs clears indapamide approximately twice as fast as humans.

Semiautomated assay for indapamide in biological fluids.

A sensitive fluorescence procedure for the determination of indapamide in plasma and whole blood was developed. The procedure requires preextraction of the biological sample followed by continuous-flow analysis. The assay is sensitive to indapamide levels of 25 ng/ml in plasma and blood. A linear response from 25 to 200 ng/ml is observed. The procedure also can be used to measure urinary levels of indapamide. The assay has been used to obtain whole blood and plasma level curves from subjects receiving 2.5 mg of indapamide.

Fluorometric assay for urinary indapamide.

A sensitive fluorescence method for the determination of indapamide was developed. Reaction of indapamide with sodium hydroxide at 100 degrees yielded a fluorescent product, and addition of formaldehyde to the fluorescent product increased its fluorescence intensity by a factor of three. The assay is sensitive to levels of indapamide of 0.025 microgram/ml in an aqueous solution, and a linear response between 0.025 and 2.0 microgram/ml was observed. The procedure was adapted to the analysis of intact indapamide in urine. Concentrations of indapamide of 0.05 microgram/ml can be detected in dogs given 20 mg of the drug.