N¹‐Methylnicotinamide as Biomarker for MATE‐Mediated Renal Drug–Drug Interactions: Impact of Cimetidine, Rifampin, Verapamil, and Probenecid

Abstract

N1‐methylnicotinamide (NMN) has been proposed as endogenous biomarker for drug–drug interactions mediated by inhibition of multidrug and toxin extrusion proteins (MATEs) at the renal proximal tubule. We analyzed NMN in plasma and urine samples of two clinical trials investigating a new probe drug cocktail (consisting of digoxin, metformin, furosemide, and rosuvastatin) dedicated to clinically relevant drug transporters. In trial 1, NMN was investigated after single‐dose treatment with individual cocktail components or after cocktail treatment. In trial 2, NMN was investigated after treatment with cocktail alone or with cocktail + inhibitor (cimetidine, a MATE inhibitor; or rifampin, verapamil, or probenecid, inhibitors of other transporters). In trial 1, NMN kinetics in plasma and urine were essentially not affected by individual cocktail components or after cocktail treatment. In trial 2, NMN renal clearance from 0 to 12 hours (CLR,0–12) geometric mean ratio (GMR) after cocktail + cimetidine vs. cocktail alone was 75% (90% confidence interval (CI): 65–87%). NMN CLR GMR after cocktail + verapamil, + rifampin, or + probenecid vs. cocktail alone was 99% (90% CI: 81–121%), 91% (90% CI: 75–111%), and 107% (90% CI: 91–126%), respectively. Compared with creatinine CLR and creatinine area under the plasma‐concentration time curve, NMN CLR was more specific and more sensitive for renal MATE inhibition. Absence of impact of the cocktail on NMN in trial 1 allows for utilization of NMN in studies using this transporter cocktail. Trial 2 data support that NMN CLR is a specific and sensitive marker for MATE‐mediated renal drug–drug interactions.

A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

“…Renal clearance of NMN over 12 and 24 hours appeared as a sensitive pharmacokinetic parameter for MATE‐mediated DDIs. In a recent publication, we demonstrated that cimetidine has a sensitive and specific impact on the renal clearance of NMN, if it is analyzed with a targeted method 24 . It should be noted, that, in the present study, we analyzed NMN abundance in plasma at one timepoint only (2 hours after administration of cimetidine, ~ 10:00 AM).…”

“…In a recent publication, we demonstrated that cimetidine has a sensitive and specific impact on the renal clearance of NMN, if it is analyzed with a targeted method. 24 It should be noted, that, in the present study, we analyzed NMN abundance in plasma at one timepoint only (2 hours after administration of cimetidine, ~ 10:00 AM). In accordance with the previous studies, we observed a pronounced decrease in NMN plasma concentrations due to cimetidine at this timepoint, which nearly outweighed the cimetidine-mediated decrease in NMN urinary excretion, resulting in a non-sensitive decrease in NMN renal elimination due to cimetidine.…”

“…N 1 -methylnicotinamide (NMN) [−1.12] was sensitively reduced in plasma due to treatment with cimetidine as expected from the literature. [21][22][23][24] In urine, eight endogenous molecules were sensitively reduced after cimetidine treatment. The largest decrease was observed for L-acetylcarnitine [−3.…”

Biomarkers Come of Age in Clinical Pharmacology

“…on the use of renal clearance (CL R ) of a biomarker, which can be used to predict DDIs caused by altered activity of transporters in the kidneys. 11 The paper concerns N1methylnicotinamide (NMN) and DDIs mediated by the multidrug and toxin extrusion proteins (MATEs). The study demonstrates that rather than circulating levels of NMN, CL R of NMN is the biomarker for DDIs involving MATEs.…”

“…The fourth manuscript by Muller et al 11 . goes beyond measurements of circulating levels of biomarkers to predict DDIs; instead, the paper entitled “N1‐Methylnicotinamide as Biomarker for MATE‐Mediated Renal Drug–Drug Interactions: Impact of Cimetidine, Rifampin, Verapamil, and Probenecid,” focuses on the use of renal clearance (CL R ) of a biomarker, which can be used to predict DDIs caused by altered activity of transporters in the kidneys 11 . The paper concerns N1‐methylnicotinamide (NMN) and DDIs mediated by the multidrug and toxin extrusion proteins (MATEs).…”