Biol Pharm Bull. 2026;49(10):1579-1586. doi: 10.1248/bpb.b26-00232.
ABSTRACT
Human serum albumin (HSA), the most abundant plasma protein, plays a critical role in transporting endogenous and exogenous ligands and drugs. Oxidative stress and ischemia induce structural modifications in HSA, including S-cysteinylation, sulfenylation, sulfinylation, and sulfonylation. These changes affect the Sudlow's sites and fatty acid-binding pockets, leading to altered drug affinity and pharmacokinetics. In patients with systemic inflammation or metabolic dysfunction, including sepsis, diabetes, liver disease, and cardiovascular disease, a substantial proportion-often exceeding 50%-of circulating albumin may be structurally modified. Ischemic injury produces ischemia-modified albumin via N-terminal damage, offering a rapid and reversible biomarker for hypoxia. Experimental and clinical evidence suggests that oxidative modification of HSA can either diminish or enhance drug binding, as observed with aripiprazole and methotrexate, respectively, resulting in significant interindividual variability in pharmacodynamic responses. Reduced drug-binding capacity in patients with cirrhosis and sepsis underscores the importance of evaluating albumin quality, in addition to its quantity, when optimizing drug dosing. Future work should clarify how modified HSA affects clearance pathways and whether exogenous albumin is similarly oxidized in vivo. Understanding these qualitative alterations may improve pharmacotherapy in critically ill and chronically inflamed patients.
PMID:42816409 | DOI:10.1248/bpb.b26-00232