Consequences of Renal Failure on Non-Renal Clearance of Drugs

Abstract

Kidney disease not only alters the renal elimination but also the non-renal disposition of drugs that are metabolized by the liver. Indeed, modifications in the expression and activity of intestinal and hepatic drug metabolism enzymes and uptake and efflux transporters have been reported. Accumulated uremic toxins, inflammatory cytokines, and parathyroid hormones may modulate these proteins either directly or by inhibiting gene expression. This can lead to important unintended variations in exposure and response when drugs are administered without dose adjustment for reduced renal function. This review summarizes our current understanding of non-renal clearance in circumstances of chronic and acute renal failure with experimental but also clinical studies. It also evaluates the clinical impact on drug disposition. Predicting the extent of the drug disposition modification is difficult first because of the complex interplay between metabolic enzymes and transport proteins but also because of the differential effects in the different organs (liver, intestines). Recommendations of the US FDA are presented as they may be potentially helpful tools to predict these modifications when no specific pharmacokinetic studies are available.

Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94–8862) in Individuals With Renal Impairment

“…The mechanisms underlying the reduced non-renal clearance of drugs metabolized by the liver in patients with kidney disease are thought to involve alterations in the expression and activity of intestinal and hepatic drug-metabolizing enzymes and transporters. [25][26][27] A reduction in the expression and activity of intestinal CYP enzymes in patients with kidney disease and the resulting inhibition of first-pass metabolism is believed to increase the bioavailability of some drugs. 25 Reduced hepatic CYP expression and activity, and therefore systemic metabolism of drugs, has also been reported in renal disease.…”

“…[25][26][27] A reduction in the expression and activity of intestinal CYP enzymes in patients with kidney disease and the resulting inhibition of first-pass metabolism is believed to increase the bioavailability of some drugs. 25 Reduced hepatic CYP expression and activity, and therefore systemic metabolism of drugs, has also been reported in renal disease. 25 These modifications to metabolic enzymes and transporters observed in patients with renal disease are most probably caused by the accumulation of uremic toxins.…”

“…25 Reduced hepatic CYP expression and activity, and therefore systemic metabolism of drugs, has also been reported in renal disease. 25 These modifications to metabolic enzymes and transporters observed in patients with renal disease are most probably caused by the accumulation of uremic toxins. 25 These mechanisms may explain the increased exposure to finerenone in the moderate and severe renal impairment groups.…”

Comparative pharmacokinetics of the main compounds of Shanzhuyu extract after oral administration in normal and chronic kidney disease rats

“…Renal impairment is associated with multiple physiological changes that affect the disposition of therapeutic drugs. The decreased clearance (CL) has been observed for drugs eliminated by renal and nonrenal pathways (Asconape, 2014;Lalande et al, 2014). The change may display the interplay between 2 major drug eliminating organs, the liver and the kidney.…”

Effect of Experimental Kidney Disease on the Functional Expression of Hepatic Reductases

“…CKD patients commonly exhibit unpredictable changes in drug disposition, largely resulting from decreased renal clearance of drugs excreted unchanged by the kidney, as well as altered nonrenal clearance (Nolin et al, 2008). Remarkable decreases in the functional expression of drug-metabolizing enzymes that mediate nonrenal drug clearance, particularly phase I oxidation by cytochrome P450 (P450) enzymes, have been well documented in the setting of kidney disease (Naud et al, 2012;Lalande et al, 2014;Yeung et al, 2014). Phase II conjugation via acetylation (Simard et al, 2008) is also decreased by kidney disease, but glucuronidation is not affected (Yu et al, 2006).…”