LC-MS/MS assay for N1-methylnicotinamide in humans, an endogenous probe for renal transporters

Bioanalysis. 2018 May 1;10(9):673-689. doi: 10.4155/bio-2017-0272. Epub 2018 May 11.

Abstract

Background: N1-methylnicotinamide (1-NMN) has been proposed as a potential clinical biomarker to assess drug-drug interactions involving organic cation transporters (OCT2) and multidrug and toxin extrusion protein transporters.

Results: A hydrophilic interaction liquid chromatography-MS/MS assay, to quantify 1-NMN, in human plasma and urine is reported.

Materials & methods: A hydrophilic interaction chromatography (HILIC)-tandem mass spectrometry (MS/MS) assay to quantify 1-NMN in human plasma and urine is reported. The basal 1-NMN levels in plasma and urine were 4-120 and 2000-15,000 ng/ml, respectively.

Conclusion: 1-NMN plasma AUCs increased two- to fourfold versus placebo following the administration of a clinical candidate that in vitro experiments indicated was an OCT2 inhibitor. The described hydrophilic interaction liquid chromatography-MS/MS assay can be used to assess a clinical compound candidate for the inhibition of OCT2 and multidrug and toxin extrusion protein transporter in first-in-human studies.

Keywords: HILIC–MS/MS; N1-methylnicotinamide; drug–drug interactions; endogenous biomarkers; renal transporters.

MeSH terms

  • Area Under Curve
  • Biomarkers, Pharmacological / analysis*
  • Biomarkers, Pharmacological / blood
  • Biomarkers, Pharmacological / urine
  • Chromatography, Liquid / methods
  • Data Accuracy
  • Drug Interactions
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Kidney / metabolism*
  • Niacinamide / analogs & derivatives*
  • Niacinamide / analysis
  • Niacinamide / blood
  • Niacinamide / urine
  • Organic Cation Transporter 2 / antagonists & inhibitors
  • Organic Cation Transporter 2 / metabolism*
  • Placebos
  • Reference Standards
  • Tandem Mass Spectrometry / methods

Substances

  • Biomarkers, Pharmacological
  • Organic Cation Transporter 2
  • Placebos
  • SLC22A2 protein, human
  • Niacinamide
  • N(1)-methylnicotinamide