Azosemide kinetics and dynamics.

Azosemide is a loop diuretic that may also affect sodium reabsorption at the proximal tubule. We gave intravenous and oral doses of the drug to normal subjects to examine its kinetic and dynamic parameters. In the fasting state a lag time of absorption of approximately 1 hr was followed by absorption t 1/2s and elimination t 1/2s of approximately 0.75 and 2 2.5 hr. Only 2% of an oral dose was excreted unchanged in the urine. After intravenous dosing the elimination t 1/2 was approximately 2 hr; 20% of a dose was recovered unchanged. Thus azosemide has an estimated bioavailability of 10%. The relationship between urinary azosemide excretion rate ("dose") and natriuretic response follows a sigmoid-shaped curve with a dose inducing half-maximal response of 9.3 +/- 2.6 micrograms/min, whereas it is 69.8, 12.1 and 1 microgram/min for furosemide, piretanide, and bumetanide respectively.

Absorption and disposition of furosemide in congestive heart failure.

Changes in response to furosemide and other diuretics in patients with congestive heart failure (CHF) could occur because of disease-induced changes in absorption of the drug or changes in disposition which affect its access to its site of action. A difference was not found in the bioavailability of forosemide in patients with CHF compared to normal volunteers, 31 +/- 12 vs. 38 +/- 20% (mean +/- sd), respectively. Both groups showed considerable interindividual variability, though serial analyses within individuals revealed consistency. Amounts of furosemide delivered into the urine after an intravenous dose correlated significantly to that after an oral dose implying that the interindividual variability is not caused primarily by variability in absorption in either group. Overall, disposition kinetics of furosemide did not differ between groups. Because of heterogeneity of renal and cardiac function among the patients, we were able to demonstrate correlations of plasma and renal clearance of furosemide with renal function; in turn, renal function correlated with left ventricular ejection fraction. Consequently, some patients had changes in furosemide disposition, but, for the most part, differences in response to furosemide were caused by abnormal responses to, rather than changed handling of the diuretic.

Pharmacokinetic-dynamic analysis of the indomethacin-furosemide interaction in man.

Indomethacin decreased the natriuretic response to furosemide. A possible mechanism of this effect of indomethacin, independent of prostaglandin synthetase inhibition, is a pharmacokinetic drug interaction in which indomethacin affects access of furosemide to its intratubular site of action. We administered 40 and 20 mg of furosemide to eight normal volunteers with and without pretreatment to eight normal volunteers with and without pretreatment with indomethacin. Furosemide concentration in serum and urine samples was measured by high performance liquid chromatography. Indomethacin significantly decreased plasma clearance of furosemide from 1.84 +/- 0.36 to 1.10 +/- 0.08 ml/kg/min (P < 0.2) and renal clearance of furosemide from 1.05 +/- 0.23 to 0.60 +/- 0.06 ml/kg/min (P < 0.05). The nonrenal clearance of furosemide decreased, but not significantly, from 0.80 +/- 0.17 to 0.50 +/- 0.10 ml/kg/min. Neither the total amount of furosemide delivered into the urine, nor the time course of furosemide delivery after the 40 or 20 mg doses changed with indomethacin pretreatment. Indomethacin significantly altered dose-response curves of furosemide. While the serum concentration-response curves of furosemide significantly shifted to the right, the urinary furosemide-response curve did not shift after indomethacin pretreatment. However, with both analyses, maximal response decreased. Indomethacin altered furosemide disposition and delivery into the urine. Nevertheless, this pharmacokinetic drug interaction did not account for the inhibitory effect of indomethacin on the response of furosemide.

Furosemide in patients with heart failure: shift in dose-response curves.

We studied 10 patients with congestive heart failure to assess the dynamics of their response to 40 mg of furosemide. Patients excreted less sodium than normal controls: 142 +/- 36 and 245 +/- 16 mEq/4 hr (p < 0.05). Patients delivered the same amount of furosemide into the urine--14.9 +/- 2.0 and 18.7 +/- 2.1 mg/4 hr (p < 0.20)--but the time course of delivery differed. Normal subjects had a sigmoid-shaped curve when furosemide excretion rate was related to response. All patients but one had shifts in this curve and for a number of patients the configuration differed substantially from a sigmoid curve.