The effect of chronic renal failure on drug metabolism and transport

Abstract

Background-Chronic renal failure (CRF) has been shown to significantly reduce the nonrenal clearance and alter bioavailability of drugs predominantly metabolized by the liver and intestine.Objectives-The purpose of this article is to review all significant animal and clinical studies dealing with the effect of CRF on drug metabolism and transport.Methods-The National Library of Medicine PubMed was utilized with the search terms 'chronic renal failure, cytochrome P450, liver metabolism, efflux drug transport and uptake transport' including relevant articles back to 1969.Results-Animal studies in CRF have shown a major downregulation (40-85%) of hepatic and intestinal cytochrome P450 (CYP) metabolism. High levels of parathyroid hormone, cytokines, and uremic toxins have been shown to reduce CYP activity. Phase II reactions and drug transporters such as P-glycoprotein (Pgp) and organic anion transporting polypeptide (OATP) are also affected.Conclusion-CRF alters intestinal, renal, and hepatic drug metabolism and transport producing a clinically significant impact on drug disposition and increasing the risk for adverse drug reactions.

Utility of a physiologically–based pharmacokinetic (PBPK) modeling approach to quantitatively predict a complex drug–drug–disease interaction scenario for rivaroxaban during the drug review process: implications for clinical practice

“…Second, because the majority of the published studies included primarily male subjects, extrapolation of age effects for female subjects may require further evaluation. Third, although decreased metabolism in RI was incorporated into the model, this assumption was based on relatively few published reports regarding altered metabolic activity with RI [30][31][32][33][34]. Protein binding effects were not incorporated into this model.…”

Prevalence of Ochratoxigenic Fungi and Ochratoxin A Residues in Animal Feeds and Modulation of Their Toxic Effects by Glutathione

“…These results were considered to be a more sensitive measure in evaluating liver function and damage in the sera of OTA administration (Prati et al, 2016). The more severe the liver damage was the higher release of the liver enzymes (Dreisbach and Lertora, 2008).…”

The uremic toxin oxythiamine causes functional thiamine deficiency in end-stage renal disease by inhibiting transketolase activity

“…Trace mono-oxygenase metabolism of thiamine to oxythiamine by human tissues or intestinal bacteria is possible but unknown; moreover, mono-oxygenases (cytochrome P450 enzymes) tend to be downregulated in renal failure. 18 The precedent from chemical synthesis and the dependence of kinetics and product distribution of thiamine degradation on pH and temperature suggest processing of thiamine under acidic conditions at high temperatures forms oxythiamine. 15 Model studies herein support this: oxythiamine was only formed in acidic solution at pH 2.9 heated at 100 o C. pH 2.9 is similar to the acidity of some fruits, diluted vinegar 19 and mean pH of the stomach in the prandial/postprandial period.…”