Probenecid inhibits the renal clearance of frusemide and its acyl glucuronide

The effect of oral probenecid (1 g) on the pharmacokinetics of frusemide (80 mg p.o.) and its acyl glucuronide was studied in nine healthy subjects. Probenecid significantly increased the t1/2,z of frusemide from 2.01 +/- 0.68 to 3.40 +/- 1.48 h (P = 0.0015) and significantly decreased oral clearance from 164 +/- 67.0 to 58.3 +/- 28.1 ml min-1 (P = 0.0001). No effect of probenecid on the plasma protein binding of frusemide was detected. Probenecid significantly increased the tmax of the metabolite frusemide acyl glucuronide from 1.4 to 2.6 h, but had no effect on the tlag, Cmax, t1/2,z and plasma protein binding. The urinary recoveries of unchanged frusemide (39.2 +/- 10.2 vs 34.4 +/- 8.6%, P = 0.28) and its acyl glucuronide (12.1 +/- 2.7 vs 11.8 +/- 3.7%, P > 0.8) were not altered by probenecid. However, probenecid decreased the renal clearance of both frusemide (128 +/- 49 vs 44.0 +/- 18.6 ml min-1, P = 0.0002) and the acyl glucuronide (552 +/- 298 vs 158 +/- 94.0 ml min-1, P < 0.0001). The non-renal clearance of frusemide (36.7 +/- 21.0 vs 15.2 +/- 13.4 ml min-1, P = 0.0068) was also decreased. The clinical relevance of the study relates to the possible conjugation of frusemide in the kidney and the role of the conjugate in the pharmacodynamic effect.