Overview
GW-501516, commonly known as Cardarine, is a synthetic peroxisome proliferator-activated receptor delta (PPARδ) agonist developed jointly by GlaxoSmithKline and Ligand Pharmaceuticals in the early 2000s. Originally investigated as a potential treatment for metabolic syndrome, dyslipidemia, and obesity, GW-501516 demonstrated remarkable effects on lipid metabolism, endurance capacity, and fat oxidation in preclinical and early clinical studies.
The compound gained scientific attention following a landmark 2008 study by Narkar et al., published in Cell, demonstrating that GW-501516 administration in sedentary mice increased running endurance by 68% without any exercise training. When combined with exercise, endurance gains were amplified further. This 'exercise in a pill' effect made headlines worldwide and ignited interest in PPARδ as a therapeutic target.
However, GlaxoSmithKline terminated development in 2007 after long-term animal toxicology studies revealed rapid tumor development across multiple organ systems in rats. Two-year carcinogenicity studies showed tumors in the liver, stomach, bladder, skin, thyroid, tongue, testes, ovaries, and uterus. Despite this concerning safety signal, GW-501516 has proliferated in grey-market supplements and is banned by the World Anti-Doping Agency (WADA).
This guide provides a thorough examination of GW-501516's pharmacology, the evidence behind its metabolic effects, and the critical safety concerns that led to its abandonment as a pharmaceutical candidate.
Quick facts
- Mechanism
- PPARδ agonist reprogramming muscle fiber metabolism and fat oxidation
- Primary use
- Endurance Enhancement & Fat Metabolism (Abandoned)
- Evidence
- moderate
- FDA
- Not approved
- Route
- Oral
- Typical results
- Animal studies show 50–75% increases in running endurance and significant fat oxidation enhancement
Chemical information
GW-501516 (C₂₁H₁₈F₃NO₃S₂) is a metabolic compound with a molecular weight of 453.49 g/mol. Its structural characteristics underpin its biological activity in metabolic regulation and energy homeostasis.
How GW-501516 works
GW-501516 is a potent and highly selective PPARδ agonist (EC50 ~1.1 nM) that binds to the nuclear receptor PPARδ, forming a heterodimer with retinoid X receptor (RXR). This complex translocates to the nucleus and binds PPAR response elements (PPREs) in the promoter regions of target genes, activating transcription of genes involved in fatty acid oxidation, mitochondrial biogenesis, and fiber type switching in skeletal muscle.
In skeletal muscle, GW-501516 activates a gene program that effectively reprograms type II (fast-twitch glycolytic) muscle fibers toward a type I (slow-twitch oxidative) phenotype. This involves upregulation of CPT1b (carnitine palmitoyltransferase, the rate-limiting enzyme for mitochondrial fatty acid import), ACADM and ACADL (medium and long-chain acyl-CoA dehydrogenases), and PDK4 (pyruvate dehydrogenase kinase 4, which shifts fuel utilization from glucose to fatty acids).
The metabolic reprogramming also involves massive mitochondrial biogenesis through upregulation of PGC-1α, NRF1/2, and TFAM, increasing the oxidative capacity of each muscle cell. This explains the endurance enhancement observed in animal studies—muscles can sustain oxidative metabolism for longer periods before switching to less efficient anaerobic pathways.
In the liver, PPARδ activation increases fatty acid β-oxidation while reducing de novo lipogenesis, lowering circulating triglycerides and LDL cholesterol while raising HDL. GW-501516 also suppresses hepatic gluconeogenesis, improving insulin sensitivity. However, the carcinogenicity concern arises because PPARδ activation also promotes cell proliferation and inhibits apoptosis in certain tissues, potentially enabling tumor growth.
- PPARδ nuclear receptor: Direct agonist activating fat oxidation gene programs (EC50 ~1.1 nM)
- Muscle fiber switching: Reprograms type II to type I oxidative fibers for sustained endurance
- Mitochondrial biogenesis: Upregulates PGC-1α/NRF/TFAM for increased oxidative capacity
- Fatty acid oxidation: Increases CPT1b and acyl-CoA dehydrogenase expression
- Lipid profile: Lowers triglycerides/LDL and raises HDL cholesterol
Pharmacokinetics
| Parameter | Value | Significance |
|---|---|---|
| Molecular Weight | 453.49 g/mol | Small molecule with excellent oral bioavailability |
| Half-life | ~16–24 hours | Supports once-daily oral dosing |
| Oral Bioavailability | >95% | Near-complete oral absorption; no injection needed |
| PPARδ Selectivity | EC50 ~1.1 nM (>1000x over PPARα/γ) | Highly selective for the delta isoform |
Dosing & administration
GW-501516 dosing varies by indication and individual factors. No FDA-approved dosing exists for this compound; protocols in the literature derive from limited clinical or preclinical data and practitioner experience.
Any use should be conducted under qualified medical supervision with appropriate monitoring of safety markers.
Important: These dosing ranges are not FDA-approved. Any use should be under qualified medical supervision.
Side effects & safety
Safety data for GW-501516 is primarily derived from preclinical studies and limited human data. Long-term effects in humans remain incompletely characterized.
Common
- • Dramatic endurance enhancement (50–75% in animal models)
- • Significant increases in fatty acid oxidation and fat utilization
- • Improved lipid profiles (reduced triglycerides, increased HDL)
- • Enhanced insulin sensitivity and glucose tolerance
- • Reduced inflammation through NF-κB suppression
- • Oral bioavailability (no injection required)
Serious / potential risks
- • CRITICAL: Rapid multi-organ tumor development in 2-year rat studies
- • Tumors observed in liver, stomach, bladder, thyroid, skin, tongue, testes, ovaries, uterus
- • Abandoned by GlaxoSmithKline due to carcinogenicity
- • Banned by WADA as a prohibited substance
- • Long-term human safety data does not exist
- • Grey-market products carry additional contamination risks
Drug interactions
| Medication | Interaction | Recommendation |
|---|---|---|
| Statins | Complementary lipid effects | PPARδ activation improves lipids via different mechanism than HMG-CoA reductase inhibition |
| Fibrates (PPARα agonists) | Additive PPAR pathway activation | Combining PPAR agonists may increase hepatotoxicity risk |
| Warfarin/Anticoagulants | Potential altered metabolism | PPARδ may affect CYP enzyme expression; monitor INR closely |
| Metformin | Additive metabolic effects | Both improve insulin sensitivity; monitor for hypoglycemia |
Storage & handling
Lyophilized (powder)
- • Store at -20°C to 4°C (freezer or refrigerator)
- • Protect from light and moisture
- • Stable for 12–24 months when stored properly
- • Keep in original sealed container until reconstitution
Reconstituted solution
- • Refrigerate at 2–8°C after reconstitution
- • Use bacteriostatic water for multi-dose reconstitution
- • Typical stability: 14–28 days refrigerated
- • Do not freeze reconstituted solution
Cost & availability
| Source | Cost | Notes |
|---|---|---|
| Research suppliers | Varies widely | Quality and purity vary significantly between sources |
| Compounding pharmacies | Prescription required | Higher quality assurance and purity testing |
The bottom line
GW-501516 is a metabolic compound with research interest in pparδ, endurance, fat metabolism. While preclinical evidence is encouraging, it remains investigational and is not FDA-approved. Any use should be under qualified medical supervision.
Best for
- • Researchers studying metabolic regulation and energy homeostasis
- • Individuals interested in pparδ under medical guidance
Not for
- • Self-administration without medical supervision
- • Pregnant or breastfeeding individuals
- • Individuals with contraindicated conditions
Related compounds
Frequently asked questions
References
- [1] Narkar VA, Downes M, Yu RT, et al.. AMPK and PPARδ agonists are exercise mimetics. Cell (2008). doi: 10.1016/j.cell.2008.06.051 PMID: 18674809
- [2] Wang YX, Lee CH, Tiep S, et al.. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell (2003). doi: 10.1016/S0092-8674(03)00269-1 PMID: 12714018
- [3] Luquet S, Lopez-Soriano J, Holst D, et al.. Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J (2003). doi: 10.1096/fj.03-0269com PMID: 12832285
- [4] Geiger LE, Dunsford WS, Lewis DJ, et al.. Rat carcinogenicity study with GW501516, a PPAR delta agonist. Toxicol Sci (2009). PMID: Abstract #1645