Epalrestat: Pharmacology, Pharmacokinetic Profile, Administration and AE

Introduction

Epalrestat [(5-[(1Z,2E)-2-methyl-3-phenylpropenylidene]-4-oxo-2-thioxo-3-thiazolidineacetic acid);Figure 1] is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. [1] Epalrestat, an aldose reductase inhibitor, has been received approval for use to alleviate peripheral nerve disorder in diabetic patients by decreasing intracellular sorbitol accumulation in Japan, China, and India. Researchers also validated that aldose reductase inhibitors play an anti-inflammatory role in the treatment of diabetes peripheral neuropathy. Previous studies on epalrestat concentrated on diabetic complications,multiple infammation related diseases and cancer. Furthermore, researchers found that epalrestat  increased glutathione (GSH) levels by upregulating nuclear factor erythroid 2-related factor (Nrf2) in bovine aortic endothelial cells. Te KEAP1/Nrf2 signaling pathway, as one of the main neuroprotective mechanisms, is considered an important regulator of antioxidant, antiinflammatory and mitochondrial function under stress conditions, which play important roles in the damage of DAergic neurons in Parkinson's disease. It has been reported that epalrestat has antioxidant protective effects on Parkinson's disease cell models. However, there is limited data on the potential mechanism and influence of epalrestat in protection of DAergic neurons in Parkinson's disease.[2]

Pharmacology

The sorbitol (polyol) metabolic pathway, an alternative glucose reduction pathway involving the enzymes aldose reductase and sorbitol dehydrogenase, is thought to be activated by hyperglycaemic conditions. Intracellular accumulation of sorbitol during hyperglycaemia is considered to be at least partially responsible for the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat, an uncompetitive aldose reductase inhibitor, significantly reduces intracellular sorbitol accumulation in sciatic nerve, erythrocytes and ocular tissues from animal models,and in erythrocytes in humans with diabetes mellitus, without affecting glucose levels. Epalrestat also increased sodium-dependent myoinositol uptake into sciatic nerve tissue in rats and skin fibroblasts from patients with diabetes, and attenuated nerve conduction velocity and retinal changes commonly seen in patients with diabetic neuropathy and retinopathy, respectively.In healthy volunteers, distribution of epalrestat is rapid and peak plasma concentrations are reached 1 to 2 hours after oral doses of 50 to 200mg. The elimination half-life is about 1 hour,and unchanged epalrestat and sulphate conjugates of the mono- and dihydroxyphenyl metabolitesare found in the urine.[1]

Pharmacokinetic Profile

Limited data are available on the pharmacokinetic properties of epalrestat, and no human kinetic studies are published in English. According to epalrestat’s package insert, a peak plasma concentration of 3.9 µg/ml is reached approximately 1 hour after administration of a 50-mg oral dose to healthy adults before meals, resulting in an area under the plasma concentration–time curve from time zero extrapolated to infinity of 6.4 µg•hour/ml. Metabolism occurs in the liver by phase 1 and phase 2 reactions.During phase 1 metabolism, epalrestat is metabolized through hydroxylation into two metabolites, monohydroxy and dihydroxy compounds.The enzyme responsible for phase 1 metabolism is unknown. These compounds are further metabolized by a phase 2 reaction to produce glucuronide and sulfate conjugates. The unchanged parent drug is excreted in the urine,as are sulfate conjugates of the two metabolites.Epalrestat is highly protein bound, with a protein binding rate of 90.1%. Pharmacokinetic studies of epalrestat have not been conducted in patients with hepatic or renal impairment, diabetes, or advanced age. No drug interactions with epalrestat have been identified[3]

Dosage and Administration

The recommended dosage of epalrestat is 50mg 3 times/day before each meal. The use of epalrestat in patients with renal and hepatic impairment has not been thoroughly evaluated;however, increases in liver function test results and in blood urea nitrogen and serum creatinine concentrations have been reported in clinical trials. The manufacturer recommends a minimum duration of 12 weeks to evaluate the efficacy of epalrestat before considering alternative therapies. According to the package insert, patients with an A1C value of 7.5% or greater, or patients with high A1C values despite the use of diet modification, exercise, and antidiabetic drugs, may receive the most benefit from the use of epalrestat.However, data from recent clinical trials suggest that epalrestat may be most effective in patients with an A1C value less than 9%. Epalrestat does not have a pregnancy category designation at this time but should only be used if the benefits outweigh the risks to the fetus, and breastfeeding should be avoided when using this drug. No published data are available regarding the use of epalrestat in pediatric patients. In addition, patients should be counseled regarding potential yellow-brown or red urine discoloration with administration of epalrestat.[3]

Adverse Effects

Epalrestat was generally safe in clinical trials at dosages of 50 mg 3 times/day or 150 mg/day. In clinical trials, the most frequently reported adverse effects were elevations in liver enzyme levels, specifically aspartate aminotransferase and alanine aminotransferase, and gastrointestinal related events such as nausea and vomiting. Table 1 lists the adverse effects reported in the reviewed clinical trials. None of the clinical trial reports stated when the adverse reactions occurred during treatment, or when the reactions resolved. However, the authors did state that the adverse effects were not serious.One incident of cerebral infarction occurred, but the authors did not further discuss the event. The manufacturer reports additional adverse effects, including serious reactions such as thrombocytopenia, fulminant hepatitis, hepatic function disorder, jaundice, and hepatic failure. The frequency of these effects is unknown, and the manufacturer recommends discontinuation of epalrestat if these effects are observed.[3]

Conclusion

Epalrestat is currently the only aldose reductase inhibitor approved to treat subjective and objective symptoms of diabetic neuropathy; however, it is approved only in Japan. The safety and efficacy of epalrestat have not yet been established internationally. Data suggest that epalrestat is well tolerated in Japanese patients and improves subjective neuropathy symptoms, nerve conduction velocity, and other nerve function tests in patients with mild-to-moderate diabetic neuropathy.

References

[1] Steele JW, Faulds D, Goa KL. Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus. Drugs Aging. 1993;3(6):532-555. doi:10.2165/00002512-199303060-00007

[2] Jia H, Liu M, Jiang H, et al. Repurposing of epalrestat for neuroprotection in parkinson's disease via activation of the KEAP1/Nrf2 pathway. J Neuroinflammation. 2025;22(1):125. Published 2025 Apr 29. doi:10.1186/s12974-025-03455-x

[3] Ramirez MA, Borja NL. Epalrestat: an aldose reductase inhibitor for the treatment of diabetic neuropathy. Pharmacotherapy. 2008;28(5):646-655. doi:10.1592/phco.28.5.646

You may like