Nephrol Dial Transplant (2003) 18: 1299-1306
© 2003 European Renal Association-European Dialysis and Transplant Association
Urinary excretion of the uraemic toxin p-cresol in the rat: contribution of glucuronidation to its metabolization
1 Renal Division and 2 Department of Pharmacology, Heymans Institute, University Hospital and 3 Laboratory of Analytical Chemistry, University of Gent, Gent, Belgium
Background. Increasing evidence indicates that lipophilic and/or protein-bound substances such as p-cresol are responsible for adverse physiological alterations in uraemic patients. To better understand the evolution of p-cresol disposition in renal failure and dialysis patients, it is necessary to determine its kinetic characteristics and biotransformation pathways.
Methods. We studied the biotransformation of p-cresol after intravenous injection of the compound in eight rats with normal renal function. Urine was collected in four 1 h intervals. To evaluate the presence of p-cresol metabolites, ß-glucuronidase was added to urine samples and the isolated unidentified chromatographic peak observed in previous experiments was submitted to tandem mass spectrometry (MS/MS) analysis.
Results. Administration of p-cresol produced a p-cresol peak and an unknown peak, suggesting biotransformation of the compound. Addition of ß-glucuronidase to urine samples and incubation at 37°C resulted in a marked decrease in the unidentified peak height (P<0.001) together with an increase in p-cresol peak height (P<0.001), suggesting that the unidentified peak was composed, at least in part, of p-cresylglucuronide. Mass spectrometry (MS) and MS/MS analysis of the isolated unidentified peak confirmed the presence of p-cresylglucuronide. Linear regression between the peak height of p-cresylglucuronide before enzyme treatment and the increase in p-cresol peak height after enzyme treatment in samples incubated with ß-glucuronidase allowed us to calculate the amount of p-cresylglucuronide as its p-cresol equivalents. This revealed that 64% of the injected p-cresol was excreted as glucuronide. There was no change in peak heights when sulphatase was added to the urine. When p-cresol and p-cresylglucuronide levels were combined, 
85% of all administered p-cresol was recovered in the urine. In addition, the combined urinary excretion of p-cresol and p-cresylglucuronide was more than four times greater than excretion of p-cresol by itself (P<0.01).
Conclusions. In rats with normal renal function, intravenous administration of p-cresol results in immediate and extensive metabolization of the compound into p-cresylglucuronide. The elimination of p-cresol from the body depends largely on the urinary excretion of this metabolite.
Keywords: creatinine; glucuronidation; kinetics; metabolization; p-cresol; rats
Correspondence and offprint requests to: Gerrit Lesaffer, Analytical Chemistry, KAHO Sint-Lieven, Gildestraat 17, Gent, Belgium. Email: gerrit.lesaffer{at}kahosl.be
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