NAD+ (nicotinamide adenine dinucleotide) — pharmacology
Molecular targets, mechanism of action, pharmacokinetics and interactions as characterised in humans.
§2Pharmacology
§2.1Molecular targets
Table 2. Molecular targets recorded for NAD+ (nicotinamide adenine dinucleotide), with the character of the interaction and the potency where the Institute holds it.
| Target | Interaction | Note |
|---|---|---|
| Oxidoreductase enzymes | Coenzyme | Hundreds of dehydrogenases; not a pharmacological target in the receptor sense |
| Sirtuins and PARPs | Substrate | Consumed rather than bound catalytically; the basis of the ageing hypothesis |
| Cell membrane | Barrier | Extracellular NAD+ does not cross the plasma membrane intact; it is degraded extracellularly to nicotinamide and other products which are then taken up. This is the central pharmacological objection to administering NAD+ itself |
§2.2Mechanism of action
NAD+ is the central redox coenzyme of intermediary metabolism and the substrate of the sirtuin and poly-ADP-ribose polymerase enzyme families. Tissue NAD+ declines with age in several species, which is the basis of interest in repletion. The Institute records a specific mechanistic objection to administering NAD+ itself: the intact dinucleotide does not cross the plasma membrane, and administered NAD+ is degraded extracellularly by CD38 and other ectoenzymes to nicotinamide and nicotinamide mononucleotide before any uptake occurs. Administering NAD+ is therefore, at best, an expensive way of administering nicotinamide.[1,2]
§2.3Pharmacokinetics
- Terminal half-life
- minutes in plasma; extracellular degradation is rapid
- Time to maximum concentration
- immediate on infusion
- Volume of distribution
- largely confined to the extracellular space when administered
- Plasma protein binding
- not applicable
- Clearance
- rapid via CD38 and other ectoenzymes
- Bioavailability
- oral bioavailability of intact NAD+ is negligible; it is hydrolysed in the gastrointestinal tract
Extracellular hydrolysis to nicotinamide, ADP-ribose and related products, followed by salvage-pathway uptake of the nicotinamide.
§2.4Interactions
- Not characterised
References cited on this page
References are numbered in order of first citation in this document. Each superscript in the text links to its entry below.
- Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism 2015;21(3):443–454. doi:10.1016/j.cmet.2015.02.009 · PMID 25738459
- Szeto HH. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. British Journal of Pharmacology 2014;171(8):2029–2050. doi:10.1111/bph.12461 · PMID 24117165
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