Mechanism of Action of Epalrestat
Epalrestat works by inhibiting aldose reductase, the key enzyme in the polyol pathway, preventing the conversion of glucose to sorbitol and reducing intracellular sorbitol accumulation that contributes to diabetic complications. 1
Biochemical Mechanism
- Epalrestat is a carboxylic acid derivative that acts as a noncompetitive and reversible aldose reductase inhibitor 1, 2
- Under hyperglycemic conditions, the polyol pathway becomes overactive, with aldose reductase converting excess glucose to sorbitol 3
- By inhibiting aldose reductase, epalrestat prevents sorbitol and fructose accumulation in nerves and other tissues 1, 4
- This inhibition helps maintain normal levels of myo-inositol in tissues, which is typically depleted in diabetic conditions 4
Pathophysiological Significance
- In diabetic neuropathy, hyperglycemia increases aldose reductase activity, leading to increased conversion of glucose to sorbitol 3
- Sorbitol accumulation in nerves causes osmotic stress and cellular damage 1
- The polyol pathway activation also leads to decreased myo-inositol levels and altered nerve function 4
- Epalrestat reverses these metabolic abnormalities by blocking the initial step in the polyol pathway 5, 2
Additional Mechanisms
- Epalrestat also alleviates oxidative stress by increasing the activities of antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase 2
- It reduces the expression of fibrotic markers such as fibronectin, collagen III, and TGF-β1 in diabetic kidney tissue 4
- Recent research suggests epalrestat may have anticancer properties through inhibition of AKR1B1 and AKR1B10 (aldose reductase isoforms) and blockade of epithelial-mesenchymal transition 6
Clinical Effects
- Epalrestat improves motor and sensory nerve conduction velocity in patients with diabetic neuropathy 1, 5
- It reduces subjective symptoms including pain, numbness, hyperesthesia, and coldness in extremities 1
- The drug improves vibration threshold and abnormal changes in heartbeat associated with diabetic peripheral neuropathy 5
- In animal models, epalrestat shows nephroprotective effects by reducing albuminuria and alleviating podocyte foot process fusion and interstitial fibrosis 4
Pharmacological Properties
- Epalrestat is orally active and brain-permeable 6
- Standard dosing is typically 50 mg three times daily 5
- The drug is well-tolerated with primarily minor adverse events, most commonly liver enzyme elevations that generally resolve with dose reduction or discontinuation 1
Epalrestat represents an important therapeutic option that addresses the underlying pathophysiology of diabetic complications rather than just providing symptomatic relief, potentially slowing disease progression in conditions like diabetic neuropathy 1, 5.