Abstract

Hyperglycaemia, a defining feature of diabetes mellitus and metabolic syndrome, exerts profound and multifaceted 
effects on drug metabolism, pharmacokinetics, and toxicity. These effects stem from coordinated disruptions in 
metabolic pathways, redox homeostasis, immune function, mitochondrial biology, and organ physiology. As global 
diabetes prevalence continues to rise, the overlap between chronic hyperglycaemia and therapeutic exposure has 
become a growing challenge in clinical pharmacology and toxicology. This review synthesizes systems-level 
insights into how hyperglycaemia modulates drug absorption, distribution, metabolism, and excretion (ADME), 
and how these changes modify susceptibility to adverse drug reactions (ADRs). We examine the cellular and 
molecular mechanisms through which elevated glucose alters enzymatic activity, transporter function, oxidative 
stress responses, inflammatory tone, and xenobiotic biotransformation. Organ-specific vulnerabilities in the liver, 
kidney, cardiovascular system, and immune system are explored, alongside emerging evidence from 
pharmacogenomics and exposomics. We also discuss the implications for dose optimization, therapeutic 
monitoring, drug–disease interactions, and precision medicine. A systems biology perspective reveals that 
hyperglycaemia not only modifies individual metabolic pathways but reconfigures entire regulatory networks, 
reshaping the toxicity landscape for numerous drug classes. Understanding these complex interactions is essential 
for improving drug safety, reducing treatment failures, and designing next-generation therapeutics for populations 
affected by chronic metabolic disease.