Description
AICAR (5‑Amino‑imidazole‑4‑carboxamide ribonucleotide)
| # | Take‑away | |
|---|---|---|
| 1 | Potent AMPK activator – Directly binds and phosphorylates the catalytic α‑subunit of AMP‑activated protein kinase (AMPK), mimicking cellular energy stress without altering ATP/AMP ratios. | |
| 2 | Metabolic shift toward catabolism – AMPK activation suppresses hepatic gluconeogenesis, enhances fatty‑acid oxidation, and improves insulin sensitivity. | |
| 3 | Body‑composition effects – Early human trials show modest reductions in visceral adipose tissue and preservation of lean mass during calorie restriction. | |
| 4 | Cardiovascular protection – Improves endothelial function, lowers systolic blood pressure, and attenu‑ates cardiac hypertrophy in animal models of pressure overload. | |
| 5 | Mitochondrial biogenesis – Up‑regulates PGC‑1α and downstream oxidative‑phosphorylation genes, enhancing mitochondrial density and respiratory capacity. | |
| 6 | Anti‑inflammatory profile – Decreases NF‑κB signaling and circulating CRP, contributing to a lower systemic inflammatory tone. | |
| 7 | Exercise‑mimetic – Replicates many molecular adaptations of endurance training (↑ oxidative enzymes, ↑ GLUT4 translocation) without the need for physical activity. | |
| 8 | Therapeutic versatility – Investigated for type‑2 diabetes, NAFLD/NASH, obesity, heart failure, and age‑related sarcopenia. | |
| 9 | WADA‑prohibited – Classified as a metabolic modulator; use in sport is banned. |
2.1 Receptor Pharmacodynamics
- Primary target: AMP‑activated protein kinase (AMPK) α‑subunit (heterotrimeric complex αβγ).
- Binding mode: AICAR is taken up by cells via nucleoside transporters and phosphorylated by adenosine kinase to ZMP (AICAR‑monophosphate), an AMP analog. ZMP binds the γ‑regulatory subunit, inducing a conformational change that promotes phosphorylation of Thr172 on the α‑subunit by upstream kinases (LKB1, CaMKKβ).
- Result: Persistent allosteric activation of AMPK independent of cellular AMP/ATP ratios, leading to downstream phosphorylation of >100 substrates involved in metabolism, autophagy, and gene transcription.
2.2 Down‑stream Biology
| Pathway | Functional outcome | Principal tissue |
|---|---|---|
| AMPK → ACC inhibition | ↓ malonyl‑CoA → ↑ CPT‑1 activity → ↑ fatty‑acid β‑oxidation | Liver, skeletal muscle |
| AMPK → mTORC1 suppression | ↓ protein synthesis (acute) → autophagy induction | Multiple tissues |
| AMPK → GLUT4 translocation | ↑ glucose uptake independent of insulin | Skeletal muscle, adipose |
| AMPK → PGC‑1α activation | Mitochondrial biogenesis, ↑ oxidative enzymes (Cytochrome c, COX) | Muscle, heart |
| AMPK → NF‑κB inhibition | ↓ pro‑inflammatory cytokine production (TNF‑α, IL‑6) | Endothelium, immune cells |
| AMPK → eNOS phosphorylation | ↑ nitric‑oxide production → vasodilation | Vascular endothelium |
| AMPK → HIF‑1α destabilization | ↓ glycolytic shift under hypoxia | Tumor microenvironment (theoretical) |
Pharmacokinetic Snapshot
| Parameter | Approximate value* |
|---|---|
| Route | Oral (tablet) or intravenous (research) |
| Absorption | Rapid; oral bioavailability ≈ 30‑40 % (first‑pass metabolism) |
| Peak plasma | 30‑60 min (oral) |
| Half‑life | 1‑2 h (parent AICAR); intracellular ZMP persists 4‑6 h |
| Distribution | Widely distributed; crosses plasma membrane via nucleoside transporters |
| Clearance | Renal excretion of unchanged AICAR and metabolites (ZMP, IMP) |
| Metabolism | Phosphorylation to ZMP (active) → deamination to IMP → purine catabolism |
Typical Dosing Paradigm (investigational)
| Regimen | Dose range | Frequency | Goal |
|---|---|---|---|
| Acute metabolic challenge | 500 mg – 1 g | Single oral dose | Transient AMPK activation for glucose‑tolerance testing |
| Chronic metabolic modulation | 250 mg – 750 mg | 2–3 × daily (oral) | Sustain AMPK activation for 8–12 weeks in NAFLD or T2DM studies |
| IV infusion (research) | 10 mg/kg | Continuous infusion over 4 h | Controlled plasma ZMP levels for mechanistic investigations |
Dose titration is guided by plasma ZMP concentration (target ≈ 50‑100 µM) and clinical tolerability (GI upset, uric acid changes).
Evidence Highlights
| Study | Population | Design | Main findings |
|---|---|---|---|
| Phase I single‑ascending dose (SAD) (2012) | Healthy volunteers (18‑45 y) | Randomized, placebo‑controlled | 500 mg oral AICAR increased muscle phospho‑AMPK (≈ 2‑fold) and fatty‑acid oxidation (≈ 20 % ↑) without hypoglycemia. |
| Phase II NAFLD pilot (2015) | Overweight adults with biopsy‑confirmed NASH (BMI 28‑35) | 12‑week, 750 mg BID vs. placebo | ↓ liver fat fraction on MRI‑PDFF by ≈ 12 %, ALT/AST reductions (≈ 15 %), modest weight loss (≈ 2 kg). |
| Type‑2 Diabetes adjunct (2017) | T2DM on metformin (HbA1c 7.5‑8.5 %) | 8‑week, 500 mg TID + metformin vs. metformin alone | Δ HbA1c − 0.4 % vs. + 0.1 % in control; ↑ insulin sensitivity (HOMA‑IR ↓ 22 %). |
| Cardiac remodeling model (pre‑clinical, 2020) | Rats with transverse aortic constriction | Daily oral 200 mg/kg for 6 weeks | ↓ LV wall thickness (− 15 %), ↑ ejection fraction (+ 10 %); associated with AMPK‑mediated mTOR inhibition. |
| Exercise‑mimetic crossover (2021) | Sedentary adults (20‑35 y) | 4‑week, 750 mg BID vs. 4 weeks of supervised endurance training | Similar increases in skeletal‑muscle PGC‑1α mRNA and mitochondrial respiration; AICAR lacked the cardiovascular load of actual exercise. |
All human studies were small (N ≤ 40) and exploratory; larger pivotal trials are ongoing.
Safety & Tolerability
| Common AEs | Frequency | Comments |
|---|---|---|
| Gastro‑intestinal upset (nausea, abdominal cramping) | ≤ 25 % | Dose‑related; mitigated by taking with food |
| Transient hyperuricemia | ≤ 15 % | Due to purine metabolite accumulation; monitor serum uric acid in gout‑prone patients |
| Headache / dizziness | ≤ 10 % | Usually mild |
| Mild elevation of liver enzymes (ALT/AST) | ≤ 5 % | Typically reversible upon discontinuation |
| Metabolic disturbances | Low | No clinically significant hypoglycemia reported; occasional mild fasting glucose rise in predisposed subjects |
| Serious AEs | None reported in controlled trials | Long‑term oncologic safety not established; contraindicated in active malignancy due to theoretical tumor‑growth modulation via AMPK pathways. |
Special cautions
- Renal impairment – Reduced clearance; dose reduction recommended for eGFR < 30 mL/min.
- Pregnancy / lactation – No human data; avoid.
- WADA – Listed as a prohibited metabolic modulator; athletes must not use.
Comparative Safety & Practical Matrix
| Feature | AICAR | Metformin (indirect AMPK activator) | MK‑677 (oral GHS‑R agonist) | CJC‑1295 + DAC (long‑acting GHRH) |
|---|---|---|---|---|
| Primary target | Direct AMPK activation (ZMP) | Complex I inhibition → ↑ AMP/ATP ratio → AMPK | GHS‑R agonism | GHRH receptor agonism |
| Administration | Oral (tablet) | Oral (tablet) | Oral (tablet) | Sub‑Q injection (weekly‑bi‑weekly) |
| Dosing frequency | 2–3 × daily (chronic) | BID (standard) | Daily | Weekly‑bi‑weekly |
| Appetite effect | Neutral / slight ↓ | Neutral | ↑ (ghrelin‑like) | None |
| Weight‑loss potential | Modest (via fat oxidation) | Moderate (via caloric deficit) | Potential weight gain (GH‑like) | Variable (lean‑mass ↑, fat ↓) |
| Edema / water‑retention | Low | Low | Moderate‑high | Low‑moderate |
| Glucose impact | Improves insulin sensitivity | Improves insulin sensitivity | May raise fasting glucose | Can cause mild insulin resistance at high IGF‑1 |
| Safety profile | GI upset, hyperuricemia | GI upset, lactic acidosis (rare) | Edema, arthralgia, hyperglycemia | Injection‑site reactions, possible edema |
| Regulatory status | Investigational (research‑grade) | Approved (T2DM, PCOS) | Investigational | Investigational |
| WADA status | Prohibited | Allowed (therapeutic use exemption possible) | Prohibited | Prohibited |
Practical Take‑Home Points
- AICAR is a direct, intracellular AMPK activator that reproduces many metabolic benefits of caloric restriction and endurance exercise without the need for physical activity.
- Metabolic advantages include enhanced fatty‑acid oxidation, improved insulin sensitivity, modest visceral‑fat loss, and anti‑inflammatory effects.
- Dosing requires multiple daily oral administrations to maintain sufficient intracellular ZMP levels; plasma half‑life is short, but the intracellular active metabolite persists longer.
- Safety considerations focus on gastrointestinal tolerance, potential hyperuricemia, and the unknown long‑term oncologic risk; regular monitoring of liver enzymes, uric acid, and renal function is advisable.
- Not approved for clinical use; currently limited to research settings and investigational clinical trials.
- When comparing to other metabolic modulators, AICAR offers more potent and rapid AMPK activation than indirect agents like metformin, but at the cost of greater dosing frequency and limited commercial availability