Comparative In Silico ADMET and Pharmacokinetic Evaluation of Metformin and Sitagliptin for Drug Repurposing in Alzheimer’s Disease

By Vasave Jamuna Rama, Pawar Sushmita Raju, Vasave Ujawala Ramesh, Gaurav Chandrakant Saupure*, Vaishali D. Shewale

NTVS Institute of Pharmacy, Nandurbar (MS), India

Published: April 2026 | DOI: 10.5281/zenodo.19850441 | Download PDF

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder requiring new therapeutic strategies. This study presents a comparative in silico ADMET and pharmacokinetic evaluation of metformin and sitagliptin. Sitagliptin demonstrated superior absorption, oral bioavailability, and blood–brain barrier penetration, indicating enhanced central nervous system availability. In contrast, metformin showed limited BBB permeability but exhibited a safer toxicity profile. Both drugs showed acceptable metabolic stability. The study suggests sitagliptin as a more promising candidate for AD repurposing, while metformin remains advantageous for long-term safety.

Keywords:

Alzheimer’s Disease, Metformin, Sitagliptin, ADMET, Pharmacokinetics, Drug Repurposing

Introduction

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β plaques, and tau pathology. Current treatments provide only symptomatic relief. Drug repurposing offers a faster and cost-effective strategy to identify new therapies. Antidiabetic drugs such as metformin and sitagliptin are being investigated due to their neuroprotective and metabolic effects.

Materials and Methods

An in silico comparative study was conducted using the DeepPK platform. Chemical structures were retrieved from PubChem in SMILES format and analyzed for ADMET parameters including absorption, distribution (with focus on BBB permeability), metabolism, excretion, toxicity, and physicochemical properties.

Results and Discussion

According to the absorption table on page 5, sitagliptin demonstrated higher intestinal absorption and oral bioavailability compared to metformin. It also showed better permeability values, indicating improved systemic exposure.

Distribution analysis (page 6) revealed that both drugs can cross the blood–brain barrier, but sitagliptin exhibited superior BBB penetration and higher volume of distribution, indicating enhanced CNS availability. Metformin’s hydrophilic nature limits its brain penetration.

Metabolic analysis showed minimal CYP450 inhibition for both drugs, indicating low drug–drug interaction risk. Sitagliptin demonstrated more flexible metabolic pathways, while metformin showed high metabolic stability.

Excretion data (page 7) indicated that sitagliptin has higher clearance and shorter half-life, reducing accumulation risk. Metformin showed longer half-life, supporting sustained exposure.

Toxicity analysis (page 7–8) showed that metformin has a safer mutagenicity profile, while sitagliptin exhibited some toxicity concerns such as mutagenicity risk. However, both drugs were non-cardiotoxic.

Conclusion

Sitagliptin demonstrates superior pharmacokinetic characteristics, especially in CNS accessibility, making it a promising candidate for Alzheimer’s disease drug repurposing. Metformin, however, offers better safety and tolerability. Further experimental and clinical studies are required to validate these findings.

References

  1. Ha J. Metformin and Alzheimer’s disease.
  2. Kosaraju J. DPP-4 inhibitors in AD.
  3. Chen Y. Pharmacokinetics of sitagliptin.
  4. Additional references as per original article.