INFLUENCE OF INDOMETHACIN ON PHARMACOKINETICS, DIURETIC RESPONSE AND HEMODYNAMICS OF FUROSEMIDE IN DOG

Abstract

Indomethacin has the potential to interact with furosemide in a number of different fashions. Some of these possibilities were investigated in 7 mongrel dogs that received furosemide (2 mg/kg i.v.). Plasma and urinary concentrations of furosemide were measured by high performance liquid chromatography, diuretic response was assessed by urinary Na excretion and renal blood flow and its distribution were estimated using the radioactive microsphere technique. Furosemide induced a prompt diuresis associated with a 50% increase in total renal blood flow. Intrarenal blood flow was preferentially increased in the inner cortical zones. Furosemide was rapidly eliminated with a renal clearance that was 35% of the total systemic clearance. Maximal Na excretion was attained at plasma furosemide concentrations greater than 0.8 .mu.g/ml; below this concentration there was a linear relationship between plasma concentration and rate of Na excretion. The ratio of Na/furosemide concentration in urine rose to a plateau, then remained constant. Indomethacin pretreatment inhibited the hemodynamic response to furosemide. In addition, indomethacin reduced the renal and extrarenal clearance of furosemide by approximately 30%, but did not change the proportion of unchanged drug excreted in the urine. Although the diuretic response for any given plasma concentration of furosemide was reduced, the ratio of urinary Na/furosemide concentration was not changed by indomethacin. Since the amount of furosemide reaching the urine was not altered, the total diuretic response was not significantly affected by indomethacin. Indomethacin alters the pharmacokinetics of the disposition of furosemide and furosemide-induced renal hemodynamic changes. The response of the renal tubule to furosemide secreted into tubular fluid was not changed by indomethacin.