Comparative In Silico ADMET and Pharmacokinetic Evaluation of Metformin and Sitagliptin for Drug Repurposing in Alzheimer's Disease
Abstract
Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β accumulation, and tau pathology. Current therapies provide only symptomatic relief, highlighting the need for disease-modifying strategies. Drug repurposing offers a time- and cost-effective approach to identify potential therapeutic candidates. Objective: This study aimed to comparatively evaluate the in silico ADMET and pharmacokinetic profiles of metformin and sitagliptin to assess their suitability for repurposing in Alzheimer’s disease. Methods: SMILES structures of both drugs were retrieved from PubChem and analyzed using the DeepPK platform. Key parameters including absorption, distribution (with emphasis on blood–brain barrier permeability), metabolism (CYP450 interactions), excretion, toxicity, and physicochemical properties were predicted and compared. Results: Sitagliptin demonstrated superior absorption characteristics, including higher predicted intestinal permeability and oral bioavailability. It also exhibited comparatively better blood–brain barrier penetration, suggesting enhanced central nervous system availability. Metformin showed limited BBB permeability but exhibited a more favorable safety profile, including lower predicted mutagenicity and toxicity risks. Both drugs displayed acceptable metabolic stability with minimal CYP450 inhibition liabilities. Sitagliptin showed a higher volume of distribution, whereas metformin…
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