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NMN IS BIOAVAILABLE AND STABLE IN BLOOD – NR IS NOT

Wikipedia: bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation

Since the Rabinowitz study in 2018, we have known that both Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN) are mostly digested in the GI tract and liver, before reaching systemic circulation.

The main difference is, if any NR reaches the bloodstream, it is unstable, and is quickly degraded to NAM (3,4).

NR is never found in the bloodstream at more than trace levels, and is not increased with supplementation.

NMN levels in the blood are increased with supplementation.

NMN IS STABLE IN THE BLOODSTREAM, NR IS NOT

Study #1:

The charts above are from the Nikiforov study which examined the stability of NAD+ and its metabolites in blood plasma. They show the degradation of NR to NAM within one hour, while NMN is stable in blood (3).

According to the authors:

NMN exhibits a relatively high chemical stability but is partly dephosphorylated to NR by the cells.

Surprisingly, NR was also rather efficiently hydrolyzed to NAM.


Study #2:

This chart is derived from the Brenner study published in August 2019. NR is found only at trace levels in the bloodstream, and is not increased after supplementation of 1,000 mg of NR per day for 3 weeks.

  • NR was found at trace levels in the blood
  • NR levels were unchanged after supplementation
  • MeNAM and Me2PY are the primary result of NR supplementation, not NR

Study #3:

The chart at left is from the Bauer study and shows the change in NR, NAM and NMN found in blood plasma after oral gavage of NR at 200 mg/kG (7).

NR was found at trace levels and not increased.

Within minutes, NAM was increased 16x, reaching 40x increase by 100 minutes.

This is a short-term increase in NAM following a single dose of NR, which shows it is degraded to NAM. This increased NAM is temporary, as excess NAM will be methylated and excreted in urine (see below).

According to the authors:

Oral NR dosing increased circulating NAM 40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood.

Orally administered NR that reaches the muscle appears to enter in the form of liberated NAM.

Study #4:

The more recent study by Canto measures the degradation of NR to NAM in blood.

This chart shows NAM levels in blood plasma massively increase two hours after oral gavage of 500 mg/kg of NR.

According to the authors:

NR quickly disappears from the bloodstream, and is almost undetectable 1 h after intraperitoneal administration at 500 mg/kg.

Elegant tracer experiments demonstrated that after oral intake, NR was utilized as such by the liver, while it predominantly reached the peripheral tissues as its degradation product, NAM.

NMN QUICKLY RAISES NMN IN LIVER AND BLOOD

mouse-single-dose

 

The chart at right is from a 2016 study in which mice were given a single dose of NMN in water.

Measurements of NMN levels in blood plasma show the NMN is quickly absorbed from the gut into blood circulation within 2–3 minutes.

NR SUPPLEMENTATION RESULTS IN EXCESS NAM WHICH IS METHYLATED AND EXCRETED IN URINE

 

When taken as oral supplements, NR is mostly degraded to NAM.

NAM levels increase initially, but excess NAM is methylated to MeNAM or Me2PY and excreted in the urine.

 

 

 

The chart at right is derived from the Brenner study that we talk about above and shows 1,000 mg of NR per day does not increase NR in the blood.

It does greatly increase NAM. When NAM levels are too high, it is methylated to MeNAM, Me2PY or Me4PY to enable excretion in the urine.

According to the authors:

Oral NR dosing increased circulating NAM 40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood.

This study shows that NR is never available in the blood in appreciable quantity.

From this chart, we see the majority is excreted in the urine as methylated NAM.

Conclusion

NMN

  • NMN IS BIOAVAILABLE AND STABLE IN BLOOD
  • NMN IS FOUND IN BLOOD AT 10X THE QUANTITY AS NR AND IS READILY AVAILABLE TO TISSUES THROUGHOUT THE BODY

NR

  • NR IS NOT STABLE IN BLOOD AND DEGRADES WITHIN ONE HOUR
  • NR IS NOT FOUND IN BLOOD AT MORE THAN TRACE LEVELS AND IS NOT AVAILABLE TO TISSUES OUTSIDE THE LIVER
  • SUPPLEMENTATION WITH NR DOES NOT INCREASE AVAILABILITY OF NR IN THE BLOODSTREAM
  • DUE TO LIMITED STABILITY, NR IS DEGRADED TO NAM BEFORE REACHING PERIPHERAL TISSUES

 

 

1.Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures (Brenner, 2019)
2. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice(Mills, 2013)
3. Degradation of Extracellular NAD+ Intermediates in Cultures of Human HEK293 Cells (Nikiforov, 2019)
4. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells (Brenner, 2016)
5. Nicotinamide mononucleotide alters mitochondrial dynamics by SIRT3‐dependent mechanism in male mice(Kristian, 2019)
6. Quantitative Analysis of NAD Synthesis-Breakdown Fluxes(Liu, Rabinowitz, 2018)
7. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle (Bauer, 2017).
8. A reduced form of nicotinamide riboside defines a new path for NAD+ biosynthesis and acts as an orally bioavailable NAD+ precursor (Canto, december 2019).