Changes In Alpha 1-acid Glycoprotein Concentration Research Articles

Influence of Desialylation on the Drug Binding Affinity of Human Alpha-1-Acid Glycoprotein Assessed by Microscale Thermophoresis.

Human serum alpha-1-acid glycoprotein (AAG) is an acute-phase plasma protein involved in the binding and transport of many drugs, especially basic and lipophilic substances. The sialic acid groups that terminate the N-glycan chains of AAG have been reported to change in response to numerous health conditions and may have an impact on the binding of drugs to AAG. In this study, we quantified the binding between native and desialylated AAG and seven drugs from different pharmacotherapeutic groups (carvedilol, diltiazem, dipyridamole, imipramine, lidocaine, propranolol, vinblastine) using microscale thermophoresis (MST). This method was chosen due to its robustness and high sensitivity, allowing precise quantification of molecular interactions based on the thermophoretic movement of fluorescent molecules. Detailed glycan analysis of native and desialylated AAG showed over 98% reduction in sialic acid content for the enzymatically desialylated AAG. The MST results indicate that desialylation generally alters the binding affinity between AAG and drugs, leading to either an increase or decrease in Kd values, probably due to conformational changes of AAG caused by the different sialic acid content. This effect is also reflected in an increased denaturation temperature of desialylated AAG. Our findings indicate that desialylation impacts free drug concentrations differently, depending on the binding affinity of the drug with AAG relative to human serum albumin (HSA). For drugs such as dipyridamole, lidocaine, and carvedilol, which have a higher affinity for AAG, desialylation significantly changes free drug concentrations. In contrast, drugs such as propranolol, imipramine, and vinblastine, which have a strong albumin binding, show only minimal changes. It is noteworthy that the free drug concentration of dipyridamole is particularly sensitive to changes in AAG concentration and glycosylation, with a decrease of up to 15% being observed, underscoring the need for dosage adjustments in personalized medicine.

Differences in the serum binding determinants of isradipine and darodipine‐consequences for serum protein binding in various diseases.

1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2. AAG was increased significantly in group II patients (P less than 0.001) and decreased in group III patients (P less than 0.001); HSA was decreased significantly in group II and group III patients (P less than 0.001). 3. The free percentage of isradipine was decreased significantly in group II patients (P less than 0.05) and increased in group III patients (P less than 0.05) and multivariate analysis showed that these variations were inversely related to changes in AAG concentration. 4. The free percentage of darodipine was increased significantly in group II and III patients (P less than 0.05) due to a decrease in HSA concentration, as shown by multivariate analysis. 5. The changes in free serum percentages of isradipine and darodipine were inversely related to concomitant changes in the concentration of the serum protein for which they showed the highest affinity, AAG for isradipine and HSA for darodipine, respectively. 6. The unexplained variability in the binding data was greater when AAG was the major determinant of binding (isradipine).

Variation in serum binding of tertatolol mediated by disease-induced modification of alpha-acid glycoprotein concentration.

The serum concentrations of alpha 1-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids, and the serum binding of tertatolol were measured in four groups of individuals: healthy control subjects (n = 24), and patients with inflammation (n = 28), and hepatic (n = 20) and renal (n = 27) insufficiency. Serum binding of tertatolol was increased in patients with inflammation (94.6%), decreased in patients with hepatic insufficiency (88.8%) and it was unchanged in patients with renal insufficiency (92.8%) as compared to controls (92.7%). Multivariate analysis indicated that the changes were mainly related to concomitant changes in AAG concentration, which could account for 57% of intersubject variability in the bound/free ratio, and to a lesser extent in HSA, which accounted for only 4% of the variability in the binding. The data show that the free fraction of the basic drug tertatolol in serum is affected by pathological conditions that cause changes in AAG concentration.

Alpha 1-acid glycoprotein concentration and serum protein binding of carbamazepine and carbamazepine-10,11 epoxide in children with epilepsy.

The relationship between the serum protein binding of carbamazepine (CBZ) and carbamazepine-10,11 epoxide (CBZ-E) and the concentration of alpha 1-acid glycoprotein (AAG) and albumin (HSA) was examined in 39 CBZ-treated epileptic children aged 4 months to 12 years. A significant inverse correlation was found between the free fraction of both compounds and serum AAG, even though changes in AAG concentration explained only part of the variation in binding. No correlation was found between the free fraction of CBZ and CBZ-E and HSA, probably due to the small intersubject variation in HSA concentration. In vitro experiments showed that both CBZ and CBZ-E were bound to HSA and to a lesser extent to AAG. At equivalent HSA concentrations, the binding of CBZ and its metabolite increased proportionately with increasing AAG concentration within the range occurring clinically.

Alpha 1-acid glycoprotein concentrations and propranolol binding in elderly patients with acute illness.

Alpha 1-acid glycoprotein (AAG) concentrations and propranolol binding were investigated in the serum of elderly hospitalized patients with acute illness, and healthy elderly and young subjects. Significantly greater AAG concentrations and reduced unbound propranolol fraction were observed in the elderly with acute disease compared to the elderly controls. The greatest changes (up to five-fold) occurred with cancer, with lesser changes associated with myocardial infarction and ischaemic heart disease, acute infection, heart failure, chronic obstructive respiratory disease, and cerebrovascular accident. Various miscellaneous conditions were also associated with high AAG concentrations and enhanced propranolol binding. The healthy elderly had higher AAG concentrations and lower unbound propranolol fractions than the healthy young group. Overall there was a highly significant correlation between the propranolol binding ratio (bound/free) and the serum AAG concentration. These results suggest that the elderly population may be particularly susceptible to changes in AAG concentrations, and that during acute illness interpretation of serum concentrations of drugs which bind mainly to AAG, may require knowledge of their free fractions.