Evidence of Hyperglycemic Levels Improving the Binding Capacity between Human Serum Albumin and the Antihypertensive Drug Hydrochlorothiazide

Abstract

Cardiovascular diseases (CVDs), especially arterial hypertension, stand as prominent contributors to global mortality. Regrettably, individuals with diabetes encounter a two-fold increase in the risk of mortality associated with CVDs. Hydrochlorothiazide (HCTZ) represents a primary intervention for hypertension, particularly in diabetic patients. Nevertheless, there has not yet been a comprehensive assessment of the biophysical characteristics regarding the impact of glucose levels on its binding affinity with human serum albumin (HSA). Thus, the present work reports the interactive profile of HSA/HCTZ in nonglycemic, normoglycemic (80 mg/dL), and hyperglycemic (320 mg/dL) conditions by time-resolved fluorescence, saturation transfer difference–nuclear magnetic resonance (STD-NMR), and surface plasmon resonance (SPR). There was a moderate ground state association of HSA/HCTZ with subdomain IIA that was affected in the presence of different glucose levels. The hyperglycemic condition decreased the binding affinity of HCTZ to subdomain IIA and increased the possibility of subdomain IB also being considered as a secondary binding site due to cooperativity and/or alterations in the protein’s structure. Overall, the glucose level under hyperglycemic conditions led to the cavities being more likely to receive more ligands, offering insights into the necessity of glucose control in the human bloodstream to not impact the residence time (pharmacokinetic profile) and pharmacotherapeutic potential of HCTZ.

Keywords

• biophysical characterization
• diabetes mellitus
• pharmacokinetic
• STD-NMR
• time-resolved fluorescence
• surface plasmon resonance