Pharmacokinetics of Bumetanide Following Intravenous, Intramuscular, and Oral Administrations to Normal Subjects

Abstract

The pharmacokinetics of bumetanide was studied in 12 normal subjects after 1-mg intravenous, intramuscular, oral solution, and tablet administrations in a random four-treatment crossover design. Plasma and urine concentrations of intact bumetanide were analyzed by a sensitive and specific RIA. The pharmacokinetics of bumetanide after intravenous administration was characterized by a biexponential equation, including an initial disposition phase (t1/2,α = 5.1 min), followed by a slower elimination phase (t1/2,β = 44 min). Bumetanide pharmacokinetics after intramuscular and oral administration could be described by a biexponential equation with first-order absorption and elimination. Bumetanide is rapidly absorbed via the intramuscular and oral routes, with mean ± SD maximum plasma concentrations of 38.2 ± 9.8 (intramuscular), 34.0 ± 10.6 (oral solution), and 30.9 ± 14.6 ng/mL (tablet) achieved within 0.34 ± 0.23, 0.76 ± 0.27, and 1.8 ± 1.2h after dosing, respectively. The drug is rapidly eliminated from the body after intravenous, intramuscular, oral solution, and oral tablet administrations, with half-lives ranging from 24–86, 47–139, 27–71, and 26–99 min, respectively. Approximately 70% of a parenteral dose and 60% of an oral dose are excreted as intact drug in urine taken 0–24h after administration. The extent of bio-availability of bumetanide from the tablet and oral solution dosage forms are equivalent, and the absolute bioavailability of the intramuscular and oral preparations are ∼100 and 80%, respectively. This is consistent with the predicted limited extent of first-pass metabolism after complete absorption of an oral dose. The pharmacokinetic and pharmacodynamic data support the conclusion that bumetanide is galenically available from the tablet dosage form and that comparable cumulative diuretic activity is obtained, regardless of the route and mode of administration.