NDT Advance Access originally published online on April 5, 2008
Nephrology Dialysis Transplantation 2008 23(7):2304-2310; doi:10.1093/ndt/gfn002
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Influences of haemodialysis on the binding sites of human serum albumin: possibility of an efficacious administration plan using binding inhibition
1 Kanazawa University Graduate School of Medical Science, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942 2 Nova Pharmacy, 1170-1 Shimowada, Yamato, Kanagawa 242-0015 3 School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka 882-8508 4 Research Institute, Shiga Medical Center, 5-4-30 Moriyama, Moriyama-City, Shiga 524-8524 5 University of Fukui Biomedical Imaging Research Center, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida, Fukui 910-1193, Japan
Correspondence and offprint requests to: Norito Takamura, Second Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, 1714-1 Yoshino, Nobeoka, Miyazaki 882-8508, Japan. Tel: +81-982-23-5537; Fax: +81-982-23-5539; E-mail: noritotaka{at}phoenix.ac.jp
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Abstract |
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Background. We have studied the possibility that low-dose treatment utilizing the inhibition that may occur between two drugs at the same site of human serum albumin (HSA) improves the pharmacological effects. The purpose is to elucidate the differences in the binding capacities of sites I and II of HSA between pre-haemodialysis (HD) and post-HD in patients with end-stage renal disease.
Methods. We evaluated free fractions of site probes, 14C-warfarin (site I) and 14C-diazepam (site II), by ultrafiltration in serum between pre-HD and post-HD. To investigate effects on the binding capacities of HSA sites, free fractions of site probes were calculated from the radioactivities measured with a liquid scintillation counter. Endogenous uraemic toxins, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), indoxyl sulphate (IS) and hippurate (HA), were determined by HPLC. Free fatty acid (FFA) as an endogenous substance was determined with an automatic multi-item simultaneous analyser.
Results. The concentrations of HSA and FFA increased significantly (post-HD/pre-HD ratio: 1.18 ± 0.10, 5.46 ± 4.91), the concentrations of IS and HA decreased significantly (post-HD/pre-HD ratio: 0.69 ± 0.10, 0.33 ± 0.15) and CMPF concentrations did not alter significantly (post-HD/pre-HD ratio: 0.97 ± 0.12, P = 0.471). The free fractions of 14C-warfarin decreased in all 14 patients at site I at post-HD compared to pre-HD (post-HD/pre-HD ratio: 0.59 ± 0.13). The free fractions of 14C-diazepam at site II remarkably decreased in 10 of 14 patients (post-HD/pre-HD ratio: 0.61 ± 0.17) and unexpectedly increased in 4 (post-HD/pre-HD ratio: 1.08 ± 0.06) post-HD compared to pre-HD. In these four patients, when we investigated the influences of these variation factors on the reduction of the binding capacities of site II, [FFA]/[HSA] increased significantly post-HD, compared to pre-HD (post-HD/pre-HD ratio: 6.91 ± 6.58). ([FFA]/[HSA] ratios of the 4 patients were from 1.22 to 3.55, the highest for the 14 patients post-HD, but the ratios of the other 10 were below 1.2 post-HD.)
Conclusion. The binding capacity of site II was unexpectedly decremented by the effects of the remarkable elevation of FFA. Therefore, monitoring the binding capacity of site II in HD is important for patients with end-stage renal disease in the efficacious administration plan using the binding inhibition of HSA.
Keywords: binding site; free fatty acid; haemodialysis; human serum albumin; protein binding
Received for publication: 11. 5.07
Accepted in revised form: 31.12.07