Factors Impacting the Estimation of Renal Clearance of N1‐methylnicotinamide, an Endogenous Probe for Renal Cation Transporters

Abstract

N1‐methylnicotinamide (1‐NMN) has been previously investigated as an endogenous probe for the activity of renal transporter organic cation transporters 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2‐K (MATE1 and MATE2‐K). In drug‐drug interaction studies, 1‐NMN renal clearance was shown to decrease after the administration of OCT2, MATE1, and MATE2‐K inhibitors. We have shown that pregnancy increases the renal clearance of 1‐NMN. We investigated the factors that may impact the estimation of renal clearance using 1‐NMN such as OCT2 genotype, as well as urine and plasma collection interval duration (8, 12 and 24 hours). In addition, we assessed whether 1‐NMN renal clearance as determined by spot urine/plasma measurements or longer collection intervals were comparable under basal and induced states. Secondary analysis was conducted on blood and urine samples collected from women prescribed metformin during early‐, mid‐, and late‐pregnancy and postpartum and healthy volunteers administered rifampin. Samples were analyzed for 1‐NMN using liquid chromatography‐mass spectrometry. The renal clearance of 1‐NMN was estimated and correlated with metformin renal clearance when data were available. 1‐NMN renal clearance was higher in both mid‐ (504 ± 293 mL/min, p < 0.01) and late‐pregnancy (557 ± 305 mL/min, p < 0.01) compared to postpartum (240 ± 106 ml/min). Metformin renal clearance and 1‐NMN renal clearance were positively correlated (rs = 0.68, p < 0.0001). OCT2 G808T genotype did not appear to affect 1‐NMN renal clearance. Plasma 1‐NMN levels were highly variable throughout the day, thus a single plasma measurement was not sufficiently representative of Css,1‐NMN to estimate 1‐NMN clearance. Studies looking at the impact of urine and plasma collection interval duration and spot sampling are ongoing. As an endogenous biomarker, 1‐NMN may be useful in assessing changes in renal OCT2, MATE1, and MATE2‐K activity, however sample collection and other subject‐specific factors (e.g., diet) may impact the results.Support or Funding InformationThis work was supported in part by the Eunice Kennedy Shriver National Institute of Child Health & Human Development [Grant U10HD047892]; NIH National Center for Advancing Translational Sciences through the Clinical and Translational Science Awards Program (CTSA) [Grant UL1TR000423]; and the NIH National Institute of General Medical Sciences [Grant T32GM 007750]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health.