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The purpose of this work was to study tolmetin plasma protein binding in an experimental model of hypoalbuminemia in the rat. Hypoalbuminemia was produced by repetitive plasmapheresis, achieving a 26.2 +/- 4.6% reduction in albumin circulating levels. Rats then received a 100 mg/kg oral tolmetin dose. Control rats received oral tolmetin 10, 56 or 100 mg/kg. Tolmetin plasma protein binding was determined by an ultrafiltration technique using an in vivo pharmacokinetic approach. Plasma protein binding data for the 3 doses studies in control animals could be described considering a single binding site with Kd = 21.9 +/- 2.1 microM and N = 0.98 +/- 0.05 sites per molecule of albumin. For hypoalbuminemic rats Kd was significantly increased (p < 0.05), while there was no significant change in the number of binding site per albumin molecule (Kd = 131.6 +/- 38.1 microM and N = 1.58 +/- 0.77). Our results show that hypoalbuminemia produces a disproportionate increase in the free fraction of tolmetin, not only by reducing albumin concentration, but also by a decrease in affinity. The mechanism responsible of such changes in affinity remains to be elucidated. 相似文献
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Ana Carolina Boni Daniela Luz Ambrósio Fernanda Barbosa Cupertino Alejandro Montenegro-Montero Stela Virgilio Fernanda Zanolli Freitas Flávia Adolfo Corrocher Rodrigo Duarte Gonçalves Ally Yang Matthew T. Weirauch Timothy R. Hughes Luis F. Larrondo Maria Célia Bertolini 《Fungal biology》2018,122(6):570-582
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Gerald T. Miwa Raul F. Alvaro John S. Walsh Regina Wang Anthony Y.H. Lu 《Chemico-biological interactions》1984,50(2):189-202
In vivo experiments were conducted with ronidazole radiolabelled in the 2-14CH2-, 4,5-14C-, N14CH3- and 4-3H-positions. The hepatic protein-bound residues, assessed by the radioactivity of exhaustively washed protein samples, were independent of the radiolabel position and occurred with 4-3H loss (>80%) in excellent agreement to previous results obtained in vitro with anaerobic incubations of liver microsomes (Miwa et al., Chem. Biol. Interact., 41 (1982) 297).HPLC analysis of acid hydrolyzed in vivo protein-bound residues, obtained from [2-14CH2] ronidazole, produced a radiochromatographic profile which was virtually identical to that obtained from a similarly treated in vitro sample. Moreover, almost quantitative (76–96%) liberation of radiolabelled methylamine was obtained from hydrolysates of in vivo and in vitro residue samples formed from [N14CH3] ronidazole. With 4,5-ring labeled ronidazole the distribution of total radioactivity of the protein hydrolysate on cation exchange resin and the fraction of the residue recovered as oxalic acid were nearly identical for the in vivo and in vitro products.We interpret these data to indicate that ronidazole alkylates proteins with retention of most of the carbon framework of the molecule, in vivo. It is also concluded that the in vitro model, previously used to examine the mechanism of protein alkylation, accurately reflects the salient process initially occuring in the intact animal during the formation of protein-bound residues of this drug. 相似文献
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Photochemical reactions of fentichlor with soluble proteins 总被引:1,自引:0,他引:1
The photochemical reactions of the photoallergen fentichlor with soluble proteins have been studied. [35S]Fentichlor was shown to bind covalently to human serum albumin (HSA) when irradiated with UV light (313 nm). HSA had the ability to bind at least eight molecules of fentichlor per molecule of protein. Fractionation of fentichlor-HSA photoadducts after (a) treatment with cyanogen bromide and (b) reduction, carboxymethylation and digestion with trypsin showed that the bound fentichlor was distributed fairly evenly throughout the sequence of the HSA molecule. Fentichlor was also shown to form photoadducts with human gamma-globulin and with bovine insulin. Its binding to insulin was restricted to the B chain of the molecule. Fundamental differences between the photochemical reactions of the photo-allergens fentichlor and tetrachlorosalicylanilide (T4CS) with soluble proteins are discussed. The reactions of fentichlor with soluble proteins are not restricted to specific binding sites (unlike T4CS). Fentichlor has the potential to react photochemically with a wide range of proteins in the epidermis and dermis, to form antigens. 相似文献
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