caa a22 4500 469026685 CHVBK 20180323132732.0 cr unu---uuuuu 170328e19921001xx s 000 0 eng 10.1007/BF01977622 doi (NATIONALLICENCE)springer-10.1007/BF01977622 Capacity-limited renal glucuronidation of probenecid by humans [Elektronische Daten] A pilot V max-finding study [T. Vree, E. Van Ewijk-Beneken Kolmer, E. Wuis, Y. Hekster] 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 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 itsV max of formation. Royal Dutch Association for Advancement of Pharmacy, 1992 Clearance, renal nationallicence Glucuronates nationallicence Metabolism nationallicence Pharmacokinetics nationallicence Probenecid nationallicence Vree T. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut Van Ewijk-Beneken Kolmer E. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut Wuis E. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut Hekster Y. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut Pharmaceutisch Weekblad Kluwer Academic Publishers 14/5(1992-10-01), 325-331 0031-6911 14:5<325 1992 14 11096 https://doi.org/10.1007/BF01977622 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF01977622 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vree T. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Van Ewijk-Beneken Kolmer E. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Wuis E. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut NATIONALLICENCE 700 1- Hekster Y. Department of Clinical Pharmacy, University Hospital Nijmegen, P.O. Box 9101, 6500, HB Nijmegen, The Netherlands aut NATIONALLICENCE 773 0- Pharmaceutisch Weekblad Kluwer Academic Publishers 14/5(1992-10-01), 325-331 0031-6911 14:5<325 1992 14 11096 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer