Kinetics of the protein-bound, lipophilic, uremic toxin p-cresol in healthy rats

P-Cresol, a partially lipophilic and protein-bound compound is related to several biochemical alterations in uremia. Because p-cresol kinetics have never been studied, we investigated its kinetic behavior in rats. Results were compared with those obtained with creatinine, a water soluble, non-protein-bound uremic retention solute, which is currently used as a marker of uremic retention. Healthy rats were divided into 3 groups with comparable body weight: (1) a control group (n=6); (2) a group (n=7) which received an intravenous bolus of 3 mg p-cresol; and (3) a group (n=5) which received an intravenous bolus of 18 mg creatinine. Blood samples were collected at 0, 5, 30, 60, 120, 180 and 240 minutes after administration for the determination of p-cresol and creatinine. Urine was collected at 1-hour intervals. p-Cresol concentrations were assessed by HPLC. Pharmacokinetic parameters of p-cresol and creatinine were calculated from the serum concentration-time curves using non-compartmental analysis. Each compound showed a concentration at time point 5 min (p-cresol: 6.7 +/- 1.4 mg/L and creatinine: 141 +/- 12 mg/L) which was comparable with values observed in uremic patients; these concentrations decreased gradually towards min 240 (p-cresol: 0.6 +/- 0.3 mg/L and creatinine: 4 +/- 2 mg/L, p<0.05 vs. 5 min in both cases). No p-cresol was found in the serum of control rats and these rats showed no changes in serum concentration of creatinine. Urinary excretions were strikingly different (p-cresol: 23 +/- 10% and creatinine: 95 +/- 25% of the administered dose, p<0.05). The half-life of p-cresol was twice as long as that of creatinine (1.5 +/- 0.8 vs. 0.8 +/- 0.1 h, p<0.05). Total clearance (CLt) was much higher for p-cresol than for creatinine (23.2 +/- 4.5 vs. 8.1 +/- 0.4 mL/min/kg, p<0.01); renal clearance (CLr), however, was substantially lower for p-cresol (4.8 +/- 2.0 vs. 8.2 +/- 1.9 mL/min/kg, p<0.05). Whereas CLt and CLr were similar for creatinine, CLt of p-cresol largely exceeded its CLr (p<0.05). The volume of distribution (Vd) was also much larger for p-cresol than for creatinine (2.9 +/- 1.4 vs. 0.6 +/- 0.1 L/kg, p<0.01). After injection of p-cresol, an additional chromatographic peak appeared in serum and in urine samples. Although at min 240 serum concentration of p-cresol had decreased to 10% of the peak value, only 23% of the administered amount was excreted in the urine and the CLr was +/- 50% lower compared to that of creatinine. Non-renal clearance and Vd of p-cresol were, however, substantially larger. These data may be of value to explain the different behavior of p-cresol in renal failure and dialysis, compared to creatinine.