Serum albumin and alpha-1 acid glycoprotein (HSA/AGP)

Serum albumin (UniProt P02768) and alpha-1 acid glycoprotein (UniProt P02763) are the two most significant plasma proteins responsible for the reversible binding and transport of drugs in the human bloodstream (UniProt; PMID: 12107040). Serum albumin is the most abundant protein in plasma and primarily binds acidic and neutral lipophilic compounds, such as warfarin and diazepam (StatPearls). In contrast, alpha-1 acid glycoprotein (AGP) is an acute-phase reactant that primarily binds basic drugs, such as propranolol and lidocaine, and its concentration can increase significantly during inflammation or infection (PMID: 12107040). While not therapeutic targets themselves, these proteins are critical determinants of a drug's pharmacokinetics and pharmacodynamics, as only the unbound (free) fraction of a drug is typically pharmacologically active. Changes in the concentrations of these proteins due to disease states like liver failure, nephrotic syndrome, or systemic inflammation can lead to significant alterations in drug efficacy and toxicity (PMID: 11510328). Understanding the binding affinity of a lead compound to these proteins is a fundamental aspect of drug development and safety assessment. Displacement of one drug by another from these binding sites can lead to clinically significant drug-drug interactions. Therefore, these proteins are monitored closely during clinical trials to predict drug distribution and clearance across different patient populations.

Other names

Human serum albuminAlpha-1-acid glycoproteinOrosomucoidAAGPlasma binding proteinsORM1ALB

These proteins act as the primary carriers for drugs in the systemic circulation. Serum albumin typically binds acidic and neutral drugs at specific sites (Sudlow sites I and II), while alpha-1 acid glycoprotein primarily binds basic and neutral lipophilic drugs. This binding sequesters the drug, limiting the free fraction available to interact with therapeutic targets and affecting the drug's half-life, distribution volume, and clearance (StatPearls: Pharmacokinetics; PMID: 11510328).