Urinary excretion of the uraemic toxin p-cresol in the rat: contribution of glucuronidation to its metabolization.

Abstract

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, beta-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 beta-glucuronidase to urine samples and incubation at 37 degrees 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 beta-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, approximately 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.

• Authors: Gerrit Lesaffer, Rita De Smet, Frans M Belpaire, Bruno Van Vlem, Marijn Van Hulle, Rita Cornelis, Norbert Lameire, Raymond Vanholder
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 18 Issue 7 Pg. 1299-306 (Jul 2003) ISSN: 0931-0509 [Print] England
• PMID: 12808165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cresols
• Glucuronides
• Toxins, Biological
• 4-cresol

Topics

• Animals
• Biotransformation
• Chromatography, High Pressure Liquid
• Cresols (metabolism, pharmacokinetics, urine)
• Disease Models, Animal
• Glucuronides (metabolism, pharmacokinetics, urine)
• Male
• Mass Spectrometry
• Rats
• Time Factors
• Toxins, Biological (metabolism, pharmacokinetics, urine)
• Uremia (metabolism, urine)