Purpose: Renal dysfunction can lead to accumulation of uremic solutes in the body. The effect of uremic solutes on the activity of CYP enzymes and transporters and its eventual effect on the clearance of drugs that are primarily cleared through the non-renal route is well documented in the literature. On the contrary, there is very limited information available on the potential effect of uremic solutes on UGT enzymes. The purpose of our project is to compile information from published literature, prescribing information (labeling) available at Drugs @FDA and commercially available databases (Pharmapendium™ and University of Washington Metabolism and Transport Drug Interaction Database) to assess whether uremic solutes can potentially affect UGT enzymes.
Methods: Using Pharmapendium and product labeling, substrates of UGT enzymes were identified based on the following criteria: UGT is indicated to play a role in metabolism and the amount of drug excreted unchanged in the urine is less than 20 %. For this subset of UGT substrates, information on increase in exposure (AUC) as a function of renal impairment was compiled using the University of Washington Metabolism and Transport Drug Interaction Database. Changes in AUC were categorized into the following three categories: Category 1 (no information is available regarding AUC or CL changes), Category 2 (mean AUC increase or CL decrease is less than 100 %), Category 3 (mean AUC increase or CL decrease is 100% or greater).
Results: From the UGT substrates identified from Pharmapendium, 86 drugs were reported to be excreted < 20 % in the urine in the unchanged form. For these 86 substrates, AUC information for subjects with renal impairment was not available for 43 substrates (Category 1). Of the remaining 43 substrates, 33 (77%) fell into Category 2 and 10 (23%) into Category 3.
Conclusion: At least 10 UGT substrates were identified that are excreted less than 20% as unchanged in the urine and yet showed mean increase in AUC by 100 % or more due to renal impairment. These findings suggest that uremic solutes may have the potential to affect UGT enzymes and thereby alter the non-renal clearance of UGT substrates. The results from well designed in vitro and in vivo studies are needed to make a definitive conclusion regarding the effect of various uremic solutes on UGT enzymes.