PHARMACODYNAMIC ANALYSIS OF THE FUROSEMIDE-PROBENECID INTERACTION IN MAN

Probenecid pretreatment in man increased the overall response to furosemide in contrast to animal studies in which probenecid decreased response by inhibiting proximal renal tubular secretion of furosemide to its active site. We administered i.v. 40 mg of furosemide to eight normal volunteers with and without probenecid pretreatment and measured serum and urinary furosemide concentrations by high performance liquid chromatography to determine the mechanism of probenecid's effect. Probenecid pretreatment significantly increased serum furosemide concentration. Urinary furosemide excretion rate paralleled urinary sodium excretion rate; both were initially decreased but were later increased by probenecid pretreatment. Probenecid pretreatment decreased renal and nonrenal clearance of furosemide (1.04 ± 0.31 vs. 0.29 ± 0.06 ml/kg/min, P<0.05; and 1.00 ± 0.18 vs. 0.27 ± 0.03 ml/kg/min, P<0.004, respectively). Although probenecid inhibited renal clearance for the duration of the study, accumulation of furosemide in serum from concomitant effects on nonrenal clearance allowed more furosemide to appear in the urine at later times, increasing response. This analysis demonstrated the importance of probenecid's effects on nonrenal elimination of furosemide in determining the overall response to furosemide. The relationship between furosemide concentrations and response depicted a sigmoid dose-response curve. Probenecid shifted the serum dose-response relationship to the right but did not affect the relationship between urinary furosemide excretion rate and response, demonstrating the importance of the urinary (as opposed to serum) concentration-response relationship of furosemide in normal man. This relationship will provide a valuable tool for assessing response to diuretics in various disease states where resistance to diuretic occurs.