The primary target of triheptanoin is the metabolic pathway of fatty acid oxidation. It acts as an anaplerotic agent by providing substrates that replenish the tricarboxylic acid (TCA) cycle intermediates. Unlike even-chain fatty acids, the odd-chain heptanoate (C7) is metabolized to both acetyl-CoA and propionyl-CoA. Propionyl-CoA is converted to succinyl-CoA, which is a key anaplerotic substrate that refills the TCA cycle. This is particularly important in conditions like lc-FAODs, where the TCA cycle is depleted due to the inefficient oxidation of long-chain fatty acids. By providing C5 ketone bodies and anaplerotic substrates, triheptanoin supports energy production and synthetic needs in the brain and other tissues.

In vitro studies have demonstrated that heptanoate, the active component of triheptanoin, is metabolized by cells independent of the enzymes required for long-chain fatty acid oxidation. In cell-based systems, the oxidation of heptanoate leads to the production of both acetyl-CoA and propionyl-CoA, which can then enter the TCA cycle. This metabolic pathway has been studied in various cell types, including hepatocytes and cardiomyocytes, to understand the compound's mechanism of action as an anaplerotic agent.

Triheptanoin is an anaplerotic chemical that can be used to bypass enzymatic flaws that obstruct long-chain amplification oxidation (LC-FAOD) by providing latent and amplifying enzymes [1]. When using calcium supplements synergistically, triheptanoin may be utilized to treat telangiectasia. By adding extra coenzyme A and propionyl coenzyme A to their TCA, along with the trianatomy (TCA) cycle intermediate enanthate (C7), triheptanoin functions as an anaplerotic agent. Triheptanoate supports the energetic hypothesis of Alzheimer's disease by increasing brain ATP consumption and mitochondrial dysfunction, including respiration and redox balance in models of the disease [2]. In the hippocampus formation of pilot pilocarpine-induced galvanic states, rats treated with triheptanoic acid (35E%) for 10 days before to pilocarpine administration maintained mitochondrial function [3].
In vivo, triheptanoin has been shown to be effective in providing metabolic fuel and improving clinical outcomes in patients with lc-FAODs. In clinical trials, patients treated with triheptanoin experienced improvements in key symptoms, including hypoglycemia, cardiomyopathy, and rhabdomyolysis. The compound is metabolized in the liver to generate ketone bodies, which can serve as an energy source for the brain and other tissues. It also replenishes TCA cycle intermediates, supporting the brain's synthetic needs.

In vitro enzyme or receptor binding assays for triheptanoin are not applicable as the compound is a substrate for metabolic enzymes rather than a direct enzyme inhibitor. However, its metabolism can be studied using in vitro systems. For example, isolated mitochondria or tissue homogenates can be incubated with heptanoate, and the production of acetyl-CoA, propionyl-CoA, and downstream metabolites can be measured using liquid chromatography-mass spectrometry (LC-MS). The activity of key enzymes in the β-oxidation pathway, such as acyl-CoA dehydrogenases, can be assessed by monitoring the rate of substrate oxidation. These assays help characterize the metabolic fate of triheptanoin and its role as an anaplerotic substrate.

In vitro cell-based assays for triheptanoin are performed using cultured cells, such as hepatocytes or fibroblasts from patients with lc-FAODs. Cells are treated with heptanoate or triheptanoin, and the effects on fatty acid oxidation, TCA cycle activity, and energy production are measured. The oxidation of [U-13C]heptanoate can be traced to assess its incorporation into TCA cycle intermediates and its contribution to anaplerosis. Additionally, cellular ATP levels and oxygen consumption rates can be measured to evaluate the compound's ability to restore mitochondrial function and energy homeostasis in cells with defective long-chain fatty acid oxidation.

Animal/Disease Models: 7-8 week old male CD1 (35-40 g)[3]
Doses: 35E% oral triheptanoic acid mixed into mouse feed
Route of Administration: 35E% triheptanoic acid treatment was given 10 days before SE induction
Experimental Results: Mitochondrial function was preserved in SE mice.
In vivo animal experiments for triheptanoin are conducted using rodent models of lc-FAODs, such as mice with a deficiency in very long-chain acyl-CoA dehydrogenase (VLCAD). The compound is typically administered orally via gavage or mixed into the diet. Efficacy is evaluated by measuring parameters such as blood glucose, plasma ketone bodies, cardiac function, and exercise tolerance. Tissue samples, including heart, liver, and skeletal muscle, are analyzed for lipid accumulation, TCA cycle intermediates, and markers of mitochondrial function. These studies demonstrate the compound's ability to bypass the metabolic defect and provide an alternative fuel source.

Absorption, Distribution and Excretion
Following a single dose of 0.3 g/kg triheptanyl glycerol, the peak plasma concentration (Cmax) was 178.9 µmol/L, the time to peak concentration (Tmax) was 0.5 h, and the area under the curve (AUC) was 336.5 µmolh/L. Following a single dose of 0.4 g/kg triheptanyl glycerol, the peak plasma concentration (Cmax) was 259.1 µmol/L, the time to peak concentration (Tmax) was 0.8 h, and the AUC was 569.1 µmolh/L. Triheptanyl glycerol is excreted in very small amounts in the urine. Following a single dose of 0.3 g/kg, the mean apparent clearance of heptanyl glycerol was 6.05 L/h/kg. Following a single dose of 0.4 g/kg, the mean apparent clearance of heptanyl was 4.31 L/h/kg.

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Metabolism/Metabolites
Triheptanoic acid glyceride hydrolyzes to heptanoic acid, which can be further metabolized to β-hydroxyvalerate or β-hydroxybutyrate.

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Biological Half-Life
Because heptanoic acid metabolites have multiple peak concentrations, the half-life of triheptanoic acid glyceride cannot be determined.
Pharmacokinetic (PK) properties of triheptanoin are characterized by its rapid metabolism. After oral administration, the compound is hydrolyzed by lipases in the gastrointestinal tract to release heptanoate, which is then absorbed and metabolized primarily in the liver. Hepatic oxidation of heptanoate generates C5 ketone bodies (β-hydroxypentanoate and β-ketopentanoate), which are exported to other tissues. The compound does not require the enzymes of long-chain fatty acid oxidation for its metabolism, making it a suitable substrate for patients with lc-FAODs. Heptanoate can enter the mitochondrion largely as a carboxylate, bypassing the carnitine shuttle system.

Hepatotoxicity
Elevated serum enzyme levels are common during trihexanol treatment, primarily reflecting the accumulation of toxic fatty acid products in muscles and the liver, as well as potential energy deficiency. In pre-registration studies, 81% of treated subjects experienced elevated creatine phosphokinase (CPK), 72% experienced elevated alanine aminotransferase (ALT), and 68% experienced elevated aspartate aminotransferase (AST). Of these, 47% of subjects had CPK levels exceeding 5 times the upper limit of normal (ULN), 24% had ALT levels exceeding 5 times the ULN, and 15% had AST levels exceeding 5 times the ULN. However, these changes were not caused by trihexanol or medium-chain triglyceride (MCT) treatment, but rather by underlying metabolic disorders and mitochondrial dysfunction. In small trials of trihexanol for other inherited metabolic disorders, no changes in laboratory parameters were reported during supplemental treatment. Despite limited clinical experience with trihexanol since its approval and widespread use, no clinically significant cases of liver injury have been published in association with this drug.
Probability Score: E (Unlikely to be the cause of clinically obvious liver damage).

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Protein Binding
Triheptanoic acid glyceride has a protein binding rate of approximately 80% in plasma, primarily binding to serum albumin.
Toxicology (toxicology) data for triheptanoin indicate that it is generally safe and well-tolerated when used as a nutritional therapy. As a triglyceride composed of naturally occurring fatty acids, it has a low inherent toxicity. The most common adverse effects are gastrointestinal in nature, such as diarrhea and abdominal discomfort, which are typical of medium-chain triglyceride supplementation. Long-term safety has been evaluated in clinical trials and post-marketing surveillance. The compound is not genotoxic, carcinogenic, or teratogenic at therapeutic doses. It is metabolized to physiological intermediates, and no significant accumulation of toxic metabolites has been observed.

[1]. Matt Shirley. Triheptanoin: First Approval. Drugs. 2020 Oct;80(15):1595-1600.
[2]. A J Yeo, et al. An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T). Mol Metab. 2021 Dec;54:101354.
[3]. Kah Ni Tan, et al. Triheptanoin protects against status epilepticus-induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration. J Neurochem. 2018 Feb;144(4):431-442.

Triheptanoic acid glyceride is a source of heptanoic acid fatty acids, which can be metabolized without the involvement of long-chain fatty acid oxidases. Clinical trials have shown that patients with long-chain fatty acid oxidation disorders (lc-FAODs) treated with triheptanoic acid glyceride have a lower risk of hypoglycemia, cardiomyopathy, rhabdomyolysis, and hepatomegaly. The incidence of complications in lc-FAOD patients decreased from approximately 60% to approximately 10% after the addition of triheptanoic acid glyceride. Triheptanoic acid glyceride was approved by the FDA on June 30, 2020. Triheptanoic acid glyceride is a medium-chain triglyceride. Triheptanoic acid glyceride is a synthetic medium-chain triglyceride specifically developed for nutritional support in patients with long-chain fatty acid oxidation disorders. Triheptanoic acid glyceride is administered orally via feeding tube, with the dosage adjusted according to 30% of the daily caloric requirement. Treatment with triheptanoic acid glyceride is not associated with elevated serum transaminase or bilirubin levels or clinically significant liver injury. Drug Indications Triheptanylglycerol is a medium-chain triglyceride used to provide energy and fatty acids for the treatment of long-chain fatty acid oxidation disorders (lc-FAODs). FDA Label Mechanism of Action Triheptanylglycerol is a source of heptanyl fatty acids, which are metabolized without the involvement of long-chain fatty acid oxidases. In clinical trials, patients with lc-FAODs treated with triheptanylglycerol experienced improvements in hypoglycemia, cardiomyopathy, and rhabdomyolysis. Pharmacodynamics Triheptanylglycerol is a source of medium-chain fatty acids for patients with lc-FAODs. It has a moderate duration of action and a wide therapeutic window. Patients should be informed of the risk of feeding tube dysfunction and malabsorption due to pancreatic insufficiency.
Other information: Triheptanoin is marketed under the brand name Dojolvi. It was approved by the U.S. Food and Drug Administration (FDA) in 2020 for the treatment of pediatric and adult patients with lc-FAODs. It is also being investigated for the treatment of other metabolic disorders, including glucose transporter type 1 deficiency syndrome (GLUT1-DS). The compound functions as an anaplerotic agent, replenishing TCA cycle intermediates, and is a source of heptanoate fatty acids.

C24H44O6

428.61

428.313

620-67-7

69286

Colorless to light yellow liquid（Density：0.904 g/cm3）

1.0±0.1 g/cm3

470.0±12.0 °C at 760 mmHg

195.5±19.6 °C

0.0±1.2 mmHg at 25°C

1.457

7.73

0

6

23

30

421

0

CCCCCCC(=O)OCC(COC(=O)CCCCCC)OC(=O)CCCCCC

PJHKBYALYHRYSK-UHFFFAOYSA-N

InChI=1S/C24H44O6/c1-4-7-10-13-16-22(25)28-19-21(30-24(27)18-15-12-9-6-3)20-29-23(26)17-14-11-8-5-2/h21H,4-20H2,1-3H3

2,3-di(heptanoyloxy)propyl heptanoate

TriheptanoinIND106011 UX-007 IND-106011IND 106011 UX007 UX 007 Glycerol trienanthate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~116.66 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.83 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)