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 (CLH) 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, CLH 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 steadystate 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 CLH of ER and the levels of uremic toxins.
Chronic kidney disease has long been known to alter drug disposition by reducing renal clearance of drugs and by affecting protein and tissue binding. Renal failure can also affect the nonrenal disposition of drugs that are extensively metabolized by the liver, as previously reviewed.1–5 Initially, the reduction in nonrenal clearance was believed to be caused by decreased metabolic enzyme activity in the liver, given that some of the isoforms of the cytochromes P450 (CYP450s) were found to be downregulated in rats with chronic kidney disease.6,7 More recent studies have suggested that alterations in transporter systems may also be involved,8–10 particularly when the activity of the CYP450 system is normal or not correlated with reduced clearance.11,12 A very recent study13 showed that end-stage renal disease (ESRD) impairs the nonrenal clearance of fexofenadine, most likely because of transporter inhibition, but causes no change in midazolam clearance.
The underlying mechanisms of these alterations in metabolic enzyme and transporter activities of drugs are not well characterized. As shown in a recent review, uremic toxins that accumulate in patients with renal failure may both directly (by inhibition) and indirectly (through regulation of levels of metabolizing enzymes and transporters) modulate enzyme and transporter functions in the liver and the intestine.9,1
Nondialyzable uremic toxins 3-carboxy-4-methyl-5-propyl-2-furan propanoic acid (CMPF) and indoxyl sulfate (Indox) are significantly elevated in the sera of patients with uremia, who show concentration levels approaching 800 μmol/l (Indox) and 400 μmol/l (CMPF).14 These substances are well known for inhibiting drug binding to albumin15,16 and kidney tubular secretion of organic acids.17 More recently, they have been shown to inhibit liver uptake transporters.8,18
In order to investigate the in vivo effects of ESRD on nonrenal drug disposition, we chose erythromycin (ER) as a probe substrate and carried out pharmacokinetic studies after administering oral and intravenous (i.v.) doses of ER to 12 patients with ESRD and 12 healthy subjects with normal renal function. The availability of both oral and i.v. commercial formulations of ER allows us to evaluate whether (i) hepatic clearance (CLH) of ER isdecreased in patients with ESRD, (ii) gut availability (absorption and metabolism) of ER is decreased in patients with ESRD, and (iii) plasma levels of uremic toxins, CMPF and Indox, correlate with the CLH of ER in these patients.
ER exhibits significantly reduced nonrenal clearance in patients with ESRD relative to that in healthy individuals.19,20 Kanfer et al.20 speculated that the markedly increased exposure to ER in patients with ESRD was most likely due to reduced CLH, in view of the fact that only a small fraction of ER is eliminated unchanged in urine. However, effects related to intestinal absorption and gut metabolism could not be excluded, because no parallel study with i.v. dosing of ER was conducted.
In the liver, hepatic uptake mediated by transporters is often of xenobiotics.21 ER uptake is mediated mainly by the organic anion transporter polypeptides (Oatps in rats and OATPs in humans). ER is partially metabolized by CYP3A4 to its N-demethylated metabolite but is primarily excretedunchanged in the bile by P-glycoprotein (P-gp). Therefore, compared to the hepatic metabolizing enzyme systems, the liver uptake and efflux transporters may play a more important role in ER disposition. We previously demonstrated that the uremic toxins CMPF and Indox could directly inhibit hepatic uptake and metabolism of ER in rat hepatocytes.8 The inhibitory effects of these uremic toxins may lead to the reduced CLH of ER inpatients with renal failure.
In the intestine, metabolizing enzymes and transporters also play important roles in drug exposure and disposition.22,23 Inhibition of either intestinal CYP3A4 or P-gp can decrease gut metabolism and increase blood levels of drugs that are substrates of P-gp and CYP3A.22,23 Therefore, metabolism in the gut may contribute to total clearance of ER. In rats with chronic renal failure, the activity levels of both P-gp and CYP3A have been shown to be decreased,24 probably because of the presence of uremic toxins.25 More recent studies in rats have evaluated the effects of chronic kidney disease on the differential functional expressions of uptake and efflux transporters in the intestine26 and liver.27 Alterations in the quantity or function of CYP3A4, OATPs, and P-gp in the intestine and liver of human patients with ESRD could potentially contribute to the apparent reduction in nonrenal clearance of ER.