Capacity-limited renal glucuronidation of probenecid by humans

Abstract Probenecid shows dose-dependent pharmacokinetics. When in one volunteer the dose is increased from 250 to 1,500 mg orally, thet 1/2 increased from 3 to 6 h. TheC max 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. Thet max rema...ined 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: Ausführliche Beschreibung Beschreibung ausblenden

1. Person:	Vree, T. B.
Weitere Personen:	Ewijk-Beneken Kolmer, E. W. J.; Wuis, E. W.; Hekster, Y. A.
Quelle:	in Pharmacy world & science : PWS ; a journal dedicated to rational drug use Vol. 14 (1992), p. 325-331 Weitere Artikel
Format:	Online-Artikel
Genre:	Clearance, renal, Glucuronates, Metabolism, Pharmacokinetics, Probenecid
Sprache:	English
Veröffentlicht:	1992
Beschreibung:	Online-Ressource
Online Zugang:	Online
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Anmerkung:	Copyright: Copyright 1992 Royal Dutch Association for Advancement of Pharmacy