PROBENECID INHIBITS THE RENAL CLEARANCE OF FRUSEMIDE AND ITS ACYL GLUCURONIDE

The effect of oral probenecid (1 g) on the pharmacokinetics of frusemi de (80 mg p.o.) and its acyl glucuronide was studied in nine healthy s ubjects. Probenecid significantly increased the t(1/2,z) of frusemide from 2.01 +/- 0.68 to 3.40 +/- 1.48 h (P = 0.0015) and significantly d ecreased 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 t(max) of the metabolite frusemide acyl glucuronide from 1.4 to 2.6 h, but h ad no effect on the t(lag), C-max, t(1/2,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 d ecreased 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 frus emide (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 possibl e conjugation of frusemide in the kidney and the role of the conjugate in the pharmacodynamic effect.