Tianeptine binding to human plasma proteins and plasma from patients with hepatic cirrhosis or renal failure.

Abstract

1. The binding of tianeptine to human plasma, isolated plasma proteins, red blood cells and to plasma from patients with cirrhosis or renal failure was studied in vitro by equilibrium dialysis. 2. Tianeptine is highly bound to plasma (95%) at therapeutic concentrations (0.3‐1 microM). No saturation of the binding sites was seen. 3. Human serum albumin (HSA) was shown to be mainly responsible for this binding (94%) with a saturable process characterized by one binding site with a moderate affinity (Ka = 4.2 x 10(4) M‐1) and a non‐saturable process with a low total affinity (nKa = 1.2 x 10(4) M‐1). 4. Like many basic and amphoteric drugs, tianeptine showed a saturable binding to alpha 1‐ acid glycoprotein (AAG) with one site and a moderate affinity (Ka = 3.7 x 10(4) M‐1). Its binding to lipoproteins and red blood cells (RBC) was weak and non‐saturable. Over the range of therapeutic drug concentrations (0.3‐1 microM), the unbound fraction in blood remains constant (4.5%). 5. Interactions were studied using non‐esterified fatty acids (NEFA) at pathological concentrations; they altered tianeptine binding to plasma and to isolated HSA. Tianeptine seems to bind to a HSA site different from sites I (warfarin) and II (diazepam), but close to site II. It also shares the only basic‐site on AAG. However, at therapeutic drug concentrations (0.3‐1 microM), not all of these interactions occur. 6. The binding of tianeptine varied according to HSA, AAG and NEFA concentrations both in patients and healthy subjects. In patients with chronic renal failure having high NEFA concentrations the unbound fraction of tianeptine (fu) increased from 0.045 to 0.153 compared with normal (P less than 0.001). In cirrhotic patients, with relatively low HSA concentrations, the fu of tianeptine increased from 0.045 to 0.088 compared with normal (P less than 0.01). 7. Multiple regression analysis of all of the data indicated that the fu of tianeptine was related significantly to HSA, NEFA and AAG concentrations, with a particularly strong correlation with NEFA concentrations. Therefore, variation of HSA and NEFA concentrations in patients on maintenance therapy may cause an increase of tianeptine fu.

Toxicity of Free p-Cresol: A Prospective and Cross-Sectional Analysis

“…Albumin is the most important binding protein for many acidic and basic drugs (26,27 ). The results of our in vitro study suggest that p-cresol also has an affinity for albumin because the in vitro decrease in the BSA concentration led to a higher free fraction of p-cresol (Fig.…”

Water proton relaxation in solutions of serum albumin from healthy donors and patients with liver and renal failures

“…The ligand loadings of HSA are different for renal and liver insufficiencies [31,32]. However an increase in blood concentration of longchain fatty acids is a common feature for these patients [2,33].…”

“…Modified forros o f human serum albumin (HSA) with lowered binding affinity were found in patients with renal and liver failures [1,2]. This results in blocking the H S A binding sites by high concentration o f endogenous hydrophobic and amphiphilic rnetabolites [1,3].…”

Determination of tianeptine in human plasma using high-performance liquid chromatography with fluorescence detection

“…Behavioral tests in rats [6,7] and clinical trials in man [8,9] have clearly demonstrated the antidepressant activity of this drug. Zini et al [10] were studied the plasma binding of TIA in humans. Ortiz et al [11] were reported the antidepressant drug TIA on plasma and platelet serotonin concentrations in the rat.…”