Pharmaceutisch Weekblad

, Volume 14, Issue 5, pp 325–331 | Cite as

Capacity-limited renal glucuronidation of probenecid by humans

A pilotVmax-finding study
  • T. B. Vree
  • E. W. J. Van Ewijk-Beneken Kolmer
  • E. W. Wuis
  • Y. A. Hekster
Practice/Case Reports


Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet1/2 increased from 3 to 6 h. TheCmax was 14μg/ml with a dosage of 250 mg, 31μg/ml with 500 mg, 70μg/ml with 1,000 mg and 120μg/ml with 1,500 mg. Thetmax remained 1 h for all four dosages. The AUC/dose ratio increased with the dose, indicating nonlinear elimination. The total body clearance declined from 64.5 ml/min for 250 mg to 26.0 ml/min for 1,500 mg. The renal clearance of probenecid remained constant, 0.6–0.8 ml/min. Protein binding of probenecid is high (91%) and independent of the dose. The phase I metabolites show lower protein binding values (34–59%). The protein binding of probenecid glucuronidein vitro (spiked plasma) is 75%. Probenecid is metabolized by cytochrome P-450 to three phase I metabolites. Each of the metabolites accounts for less than 10% of the dose administered; the percentage recovered in the urine is independent of the dose. The main metabolite probenecid glucuronide is only present in urine and not in plasma. The renal excretion rate-time profile of probenecid glucuronide shows a plateau value of approximately 700μg/min (46 mg/h) with acidic urine pH. The duration of this plateau value depends on the dose: 2 h at 500 mg, 10 h at 1,000 mg and 20 h at 1,500 mg. It is demonstrated that probenecid glucuronide must be formed in the kidney during its passage of the tubule. The plateau value in the renal excretion rate of probenecid value reflects itsVmax of formation.


Clearance, renal Glucuronates Metabolism Pharmacokinetics Probenecid 


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Copyright information

© Royal Dutch Association for Advancement of Pharmacy 1992

Authors and Affiliations

  • T. B. Vree
    • 1
  • E. W. J. Van Ewijk-Beneken Kolmer
    • 1
  • E. W. Wuis
    • 1
  • Y. A. Hekster
    • 1
  1. 1.Department of Clinical PharmacyUniversity Hospital NijmegenHB NijmegenThe Netherlands

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