Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid. A pilot experiment.
The aim of this pilot study was to demonstrate the possible inhibitory effect of probenecid on the renal glucuronidation and on the renal clearance of nalidixic acid in a human volunteer. Under acidic urine conditions, hardly any nalidixic acid is excreted unchanged (0.2%). It is excreted as acyl glucuronide (53.4%), 7-hydroxymethylnalidixic acid (10.0%), the latter's acyl glucuronide 30.9%, and 7-carboxynalidixic acid (4.2%). Under probenecid co-medication the renal glucuronidation of nalidixic acid is reduced from 53% to 16%; the renal clearance of both nalidixic acid and 7-hydroxymethylnalidixic acid are reduced (p < 0.001); the intrinsic t1/2 of the metabolite 7-hydroxymethylnalidixic acid increased from 0.48 h to 4.24 h. The amount of acyl glucuronidation of 7-hydroxymethylnalidixic acid was not altered. The in vitro protein binding of both acyl glucuronides was increased, while no effect on the unconjugated compounds was seen. Nalidixic acid had no effect on the maximal renal excretion rate of probenecid acyl glucuronide.
Vree
T B
TB
Department of Clinical Pharmacy, Sint Radboud Hospital, University of Nijmegen, The Netherlands.
Van den Biggelaar-Martea
M
M
Van Ewijk-Beneken Kolmer
E W
EW
Hekster
Y A
YA
D003864:Depression, Chemical; D005965:Glucuronates / Q000097:blood / Q000652:urine; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009268:Nalidixic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D010865:Pilot Projects; D011339:Probenecid / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding
D005965:Glucuronates; C025188:7-carboxynalidixic acid; C012368:7-hydroxynalidixic acid; D009268:Nalidixic Acid; D011339:Probenecid