Hepatic clearance, but not gut availability, of erythromycin is altered in patients with end-stage renal disease

Abstract

Nonrenal clearance of drugs can be significantly lower in patients with end-stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL(H)) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route-randomized, two-way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL(H) decreased 31% relative to baseline values (0.35 +/- 0.14 l/h/kg vs. 0.51 +/- 0.13 l/h/kg, P = 0.01), with no change in steady-state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL(H) of ER and the levels of uremic toxins.

Figure 1

Mean plasma concentrations of (a) erythromycin and (b) N-demethyl-erythromycin after intravenous infusion of erythromycin (125 mg) in subjects with end-stage renal disease (ESRD) (open circles) and in those with normal renal function (closed circles). Each symbol represents the mean ± SEM (n = 12).

Figure 1

Mean plasma concentrations of (a) erythromycin and (b) N-demethyl-erythromycin after intravenous infusion of erythromycin (125 mg) in subjects with end-stage renal disease (ESRD) (open circles) and in those with normal renal function (closed circles). Each symbol represents the mean ± SEM (n = 12).

Figure 2

Mean plasma concentrations of (a) erythromycin and (b) N-demethyl-erythromycin after oral administration of erythromycin (250 mg) in subjects with end-stage renal disease (ESRD) (open circles) and in those with normal renal function (closed circles). Each symbol represents the mean ± SEM (n = 12).

Figure 2

Mean plasma concentrations of (a) erythromycin and (b) N-demethyl-erythromycin after oral administration of erythromycin (250 mg) in subjects with end-stage renal disease (ESRD) (open circles) and in those with normal renal function (closed circles). Each symbol represents the mean ± SEM (n = 12).

Figure 3

Scatter plot of individual levels (average of 0- and 14-h measurements) of (a) 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and (b) indoxyl sulfate (Indox) vs. hepatic clearance (CL_H) in subjects with end-stage renal disease (open symbols) and in those with normal renal function (closed symbols). The plasma levels of CMPF and Indox are log transformed.

Figure 3

Scatter plot of individual levels (average of 0- and 14-h measurements) of (a) 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and (b) indoxyl sulfate (Indox) vs. hepatic clearance (CL_H) in subjects with end-stage renal disease (open symbols) and in those with normal renal function (closed symbols). The plasma levels of CMPF and Indox are log transformed.