An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers
Sophia E Airhart, Laura M Shireman, Linda J Risler, Gail D Anderson, G A Nagana Gowda, Daniel Raftery, Rong Tian, Danny D Shen, Kevin D O'Brien, Sophia E Airhart, Laura M Shireman, Linda J Risler, Gail D Anderson, G A Nagana Gowda, Daniel Raftery, Rong Tian, Danny D Shen, Kevin D O'Brien
Abstract
Objectives: The co-primary objectives of this study were to determine the human pharmacokinetics (PK) of oral NR and the effect of NR on whole blood nicotinamide adenine dinucleotide (NAD+) levels.
Background: Though mitochondrial dysfunction plays a critical role in the development and progression of heart failure, no mitochondria-targeted therapies have been translated into clinical practice. Recent murine studies have reported associations between imbalances in the NADH/NAD+ ratio with mitochondrial dysfunction in multiple tissues, including myocardium. Moreover, an NAD+ precursor, nicotinamide mononucleotide, improved cardiac function, while another NAD+ precursor, nicotinamide riboside (NR), improved mitochondrial function in muscle, liver and brown adipose. Thus, PK studies of NR in humans is critical for future clinical trials.
Methods: In this non-randomized, open-label PK study of 8 healthy volunteers, 250 mg NR was orally administered on Days 1 and 2, then uptitrated to peak dose of 1000 mg twice daily on Days 7 and 8. On the morning of Day 9, subjects completed a 24-hour PK study after receiving 1000 mg NR at t = 0. Whole-blood levels of NR, clinical blood chemistry, and NAD+ levels were analyzed.
Results: Oral NR was well tolerated with no adverse events. Significant increases comparing baseline to mean concentrations at steady state (Cave,ss) were observed for both NR (p = 0.03) and NAD+ (p = 0.001); the latter increased by 100%. Absolute changes from baseline to Day 9 in NR and NAD+ levels correlated highly (R2 = 0.72, p = 0.008).
Conclusions: Because NR increases circulating NAD+ in humans, NR may have potential as a therapy in patients with mitochondrial dysfunction due to genetic and/or acquired diseases.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- Kolwicz SC Jr., Purohit S, Tian R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ Res. 2013;113(5):603–16. doi:
- Marin-Garcia J, Goldenthal MJ. Mitochondrial centrality in heart failure. Heart Fail Rev. 2008;13(2):137–50. doi:
- Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356(11):1140–51. doi:
- Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. Journal of the American College of Cardiology. 2013;61(6):599–610. doi:
- Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013;113(6):709–24. doi:
- Nickel A, Loffler J, Maack C. Myocardial energetics in heart failure. Basic research in cardiology. 2013;108(4):358 doi:
- Wang W, Karamanlidis G, Tian R. Novel targets for mitochondrial medicine. Sci Transl Med. 2016;8(326):326rv3 doi:
- Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC, Suthammarak W, Gong G, et al. Mitochondrial Complex I Deficiency Increases Protein Acetylation and Accelerates Heart Failure. Cell Metabolism. 2013;18 doi:
- Lee CF, Garcia-Menendez L, Karamanlidis G, Tian R. Restoration of NADH/NAD ration delays pressure overload-induced cardiac dysfunction via regulation of mitochondrial protein acetylation and permeability transition. Circulation. 2013;128:A15979 (abstr)
- Hsu CP, Oka S, Shao D, Hariharan N, Sadoshima J. Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes. Circ Res. 2009;105(5):481–91. doi:
- Yamamoto T, Byun J, Zhai P, Ikeda Y, Oka S, Sadoshima J. Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and reperfusion. PLoS One. 2014;9(6):e98972 doi:
- Canto C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism. 2012;15(6):838–47. doi:
- Team RC. R: A language and environment for statistical computing. R Foundation for Statistical Computing; Internet: Vienna, Austria: 2015. [.
- Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag New York; 2009.
- Creeke PI, Dibari F, Cheung E, van den Briel T, Kyroussis E, Seal AJ. Whole blood NAD and NADP concentrations are not depressed in subjects with clinical pellagra. J Nutr. 2007;137(9):2013–7.
- Trammell SA, Schmidt MS, Weidemann BJ, Redpath P, Jaksch F, Dellinger RW, et al. Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun. 2016;7:12948 doi:
- Guyton JR, Bays HE. Safety considerations with niacin therapy. Am J Cardiol. 2007;99(6A):22C–31C. doi:
- Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–45. doi:
- Ratajczak J, Joffraud M, Trammell SA, Ras R, Canela N, Boutant M, et al. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nat Commun. 2016;7:13103 doi:
- Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metabolism. 2011;14(4):528–36. doi:
- Wielgus-Kutrowska B, Kulikowska E, Wierzchowski J, Bzowska A, Shugar D. Nicotinamide riboside, an unusual, non-typical, substrate of purified purine-nucleoside phosphorylases. Eur J Biochem. 1997;243(1–2):408–14.
- Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013;155(7):1624–38. doi:
- Santidrian AF, Matsuno-Yagi A, Ritland M, Seo BB, LeBoeuf SE, Gay LJ, et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest. 2013;123(3):1068–81. doi:
Source: PubMed