Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure.
BACKGROUND
p-cresol, which is extensively metabolized into p-cresylglucuronide in the rat, is related to several biochemical and physiologic alterations in uremia and is not removed adequately by current hemodialysis strategies. The knowledge of its in vivo kinetic behavior could be helpful to improve the current removal strategies.


METHODS
We investigated the kinetic behavior of intravenously injected p-cresol (10 mg/kg) in rats with normal and decreased renal function, and compared the results with those obtained for creatinine (60 mg/kg) under similar conditions. Renal failure was obtained by 5/6 nephrectomy. Both p-cresol and p-cresylglucuronide were analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC). The relation between the p-cresylglucuronide peak height and the underlying amount of p-cresol was determined after hydrolysis of the glucuronide with beta-glucuronidase. We calculated urinary excretion of p-cresol with and without taking p-cresylglucuronide into account. In addition, total, renal, and non-renal clearance, half-life, and volume of distribution were calculated for p-cresol.


RESULTS
Over a 4-hour period, p-cresol serum concentration showed only a minimal decline in rats with decreased renal function (t1/2 = 11.7 +/- 0.4 hours), compared to rats with normal renal function (t1/2 = 1.4 +/- 0.7 hours). A similar observation was made for p-cresylglucuronide. In rats with normal renal function, 21.0 +/- 10.0% of the injected p-cresol was excreted in urine as p-cresol and 60.7 +/- 25.0% as p-cresylglucuronide; in rats with renal failure, the respective amounts were 6.7 +/- 7.5% and 32.0 +/- 25.3% (P < 0.05 vs. normal renal function) (total recovery 81.81 +/- 31.07% vs. 38.50 +/- 32.09%, P < 0.05). The volume of distribution of p-cresol was approximately 4 times larger than that of creatinine, but was not significantly affected by renal failure. Not only renal, but also non-renal and total clearance, were much lower in rats with decreased renal function.


CONCLUSIONS
The present data sheds a light on the kinetic behavior of p-cresol in uremic patients; the large volume of distribution, especially, might explain the inadequate dialytic removal of p-cresol. In addition, a substantial amount of p-cresol is removed by metabolism, and both renal and non-renal clearance are disturbed in uremia.
Lesaffer
Gerrit
G
Department of Pharmacology, Heymans Institute, University Hospital, Gent, Belgium. Gerri.lesaffer@kahosl.be
De Smet
Rita
R
D'Heuvaert
Tommy
T
Belpaire
Frans M
FM
Lameire
Norbert
N
Vanholder
Raymond
R
D000818:Animals; D003404:Creatinine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D003408:Cresols / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000652:urine; D020719:Glucuronides / Q000378:metabolism / Q000652:urine; D006868:Hydrolysis; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014511:Uremia / Q000378:metabolism*
C485699:4-cresylglucuronide; D003408:Cresols; D020719:Glucuronides; C032538:4-cresol; D003404:Creatinine