Human serum albumin-drug acidic drugs

A number of proteins are commercially available as CSPs including a-acid glycoproteins (AGP, the major plasma binding protein for basic drugs), human serum albumin (HSA, the major plasma binding protein for weakly acidic drugs), bovine serum albumin (BSA), ovomucoid (OVM), and cellobiohydro-lase (CBH) [12]. The proteins are bonded to silica and utilized in reversed-phase mode with an aqueous buffer/organic modifier eluent. Mobile-phase... 

Table 18 Human serum albumin-drug binding affinity and drug properties. rrSTi represents log k measured using an immobilized-HSA phase. nKa represents predicted log hsa-represents log k of acidic compounds at pH 7.4. k represents log k of basic compounds at pH 7.4. MIFa and MIFb represents the molecular interaction energy values of acidic and basic compounds, resepectively. nKs represents log nST measured using a modified Hummel-Dreyer method. nJQ, nKs, nSTg and nKj represent values. PB and PB2 represent the binding %. Log Pc are predicted log P values, and log Pm are measured values. 7.4 represents pH 7.4. Reproduced by permission of Bentham Science, ref. 20.

Bluestone, R., I. Kippen, J. R. Klinenberg, and M. Whitehouse Effect of some uricosuric and anti-inflammatory drugs on the binding of uric acid to human serum albumin in vitro. 

Y. Kurono, N. Ohta, T. Yotsuyanagj, K. Ikeda, Effects of Drug Binding on the Esterase-Like Activity of Human Serum Albumin. III. Evaluation of the Two Active Sites by Using Clofibric Acid as an Inhibitor , Chem. Pharm. Bull. 1981, 29, 2345 - 2350. 

A. Salvi, P. A. Carrupt, J. M. Mayer, B. Testa, Esterase-Like Activity of Human Serum Albumin toward Prodrug Esters of Nicotinic Acid , Drug Metab. Dispos. 1997, 25, 395-398. 

The viability and function tests described above are used to evaluate the hepatocytes within the slice. Up to now, tests to measure the viability of the non-parenchymal cells have not been reported. The presence of the latter cell types is one of the conceptual advantages of slices as compared to isolated hepatocytes. As some drug targeting devices are designed to target non-parenchymal cells in the liver, the development of tests for the sinusoidal cell types deserves more attention. For example, the uptake of substrates such as succinylated human serum albumin (Suc-HSA,which is specifically endocytosed by endothelial cells [79]), or hyaluronic acid [80], can be used to assess the functionality of endocytotic pathways in the endothelial cells in the liver [81]. Other modified proteins that are specifically taken up by Kupffer cells such as mannosylated HSA, may be used to assess the functionality of the endocytotic pathway in Kupffer cells [79]. Another parameter which can be used to assess the functionality of these non-parenchymal liver cells, is the excretion of cytokines in response to pro-inflammatory stimuli. Non-parench5mal cell function in liver slices will be described in more detail in the Section 12.7. 

Human serum albumin (HSA) is an important transporter of fatty acids, metabolites, drugs, and organic compounds in the circulatory system [93, 94], It is a single polypeptide chain consisting of 585 amino acids. Under physiological conditions (pH 7), HSA adopts a heart-shaped three-dimensional (3D) structure with three homologous domains I—III (Fig. 14) each domain contains two subdomains A and B, which consist of four and six a-helices, respectively [95, 96]. The X-ray structure shows that two halves of the albumin molecule... 

Landry, F. B., Bazile, D. V., Spenlehauer, G., Veillard, M., and Kreuter, J. (1998), Peroral administration of 14C-poly(D,L-lactic acid) nanoparticles coated with human serum albumin or polyvinyl alcohol to guinea pigs,/. Drug Target., 6(4), 293-307. 

Etacrynic acid interacts with human serum albumin and modifies its binding properties (45). Since it binds to two binding sites on albumin, the benzodiazepine binding site and the warfarin binding site, it can displace drugs that bind at those sites (46). It competitively displaced 7-hydroxymethotrexate from its binding proteins in vitro (47). The clinical significance of this effect is not known. 

Fehske KJ, Muller WE. High-affinity binding of ethacrynic acid is mediated by the two most important drug binding sites of human serum albumin. Pharmacology 1986 32(4) 208-13. 

An antiserum was raised by immunization of rabbits with an immunogen prepared by coupling hyoscyamine to human serum albumin and using [3H]-atropine as tracer. Atropine and hyoscyamine reacted to equal extents with the antibodies. Some structurally related drugs e.g. homatropine or scopolamine as well as atropine hydrolysis products (tropine and tropic acid) did not interfere in the assay. 

Irikura, M. Takadate, A. Goya, S. Otagiri, M., 7-alkylaminocoumarin-4-acetic acids as fluorescent-probe for studies of drug-binding sites on human serum-albumin, Chem Pharm Bull 1991, 39, 724-728... 

Plasma albumin has binding sites for various natural metabolic substances (e.g., glucose, fatty acids, bilirubin) as well as xenobiotics and drugs (e.g., digitoxin, Warfarin). While chromatographic and solubility differences from pure human serum albumin occur in some glycosylated albumins, there does... 

Test strips, which are available for the determination of about ten low-molecular mass substances (metabolites, drugs, and electrolytes) and eight enzymes [356], can be considered as precursors of optoelectronic biosensors. Efficient optoelectronic sensors based on immobilized dyes have been devised for the determination of glucose, urea, penicillin, and human serum albumin [357]. Other approaches use immobilized luciferase or horseradish peroxidase to assay ATP or NADH or, when coupled with oxidases, to measure uric acid or cholesterol. These principles have not yet been generally accepted for use in routine analysis. Thermistor devices involving immobilized enzymes or antibodies for a number of clinically relevant substances have also been described. Thermometric enzyme linked immunosorbent assays are being routinely employed for monitoring the production of monoclonal antibodies. 

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