药物与血浆蛋白结合的药理学基础及其研究进展

摘要/Abstract

摘要： 体内各种因素引起的药物与血浆蛋白结合的改变, 可能导致相应的药代动力学参数变化。本文综述了有关药物-血浆蛋白结合的基础理论和研究方法进展, 及其与药代动力学和药效相关性的理论阐述, 并运用药理学相关基础理论对其临床意义进行了深入的探讨, 总结了在常规的药物实践中如何评价药物的游离浓度监测和血浆蛋白结合的药效和临床相关性研究。

关键词: 药物-血浆蛋白结合, 药物代谢动力学, 药物效应动力学, 临床相关性

Abstract: Drug-protein binding changes involved in numerous factors in vivo may cause changes of pharmacokinetic parameters.The tendency gained from large numbers of articles overemphasized the clinical importance of these changes.However, theoretic analysis and review of available literature data indicated that changes in plasma protein binding are usually of no principle pharmacodynamic implication.And they have little effect on the clinical exposure of a patient to a drug in a practical sense. The progress is reviewed in research and current opinions on drug-plasma protein binding in pharmacological basis for pharmacokinetic consequence and clinical relevance in this article.

Key words: drug-plasma protein binding, pharmacokinetics, pharmacodynamics, clinical relevance

中图分类号:

R969.1

郭宾, 李川. 药物与血浆蛋白结合的药理学基础及其研究进展[J]. 中国临床药理学与治疗学, 2005, 10(3): 241-253.

GUO Bin, LI Chuan. Progress in research and evaluation on drug-plasma protein binding in pharmacology[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(3): 241-253.

参考文献

1 Goldstein A.The interactions of drugs and plasma proteins[J]. Pharmcol Rev, 1949;1:102-65
2 Kragh-Hansen U.Molecular aspects of ligand binding to serum albumin[J].Pharmacol Rev, 1981;33:17-53
3 Kremer JM, Wilting J, Janssen LH.Drug binding to human alpha- 1-acid glycoprotein in health and disease[J].Pharmacol Rev, 1988;40:1-47
4 Reidenberg MM, Erill S.Drug-protein binding [M].New York:Praeger Publishers, 1986
5 Meyer MC, Guttman DE.The binding of drugs by plasma proteins[J].J Pharm Sci, 1968;57:895-918
6 Oravcova J, Bohs B, Lindner W.Drug-protein binding sites. New trends in analytical and experimental methodology[J].J Chromatogr B Biomed Appl, 1996;677:1-28
7 Wright JD, Boudinot FD, UjhelyiMR.Measurement and analysis of unbound drug concentrations[J].Clin Pharmacokinet, 1996;30:445-62
8 Heringa MB, Pastor D, Algra J, Vaes WH, Hermens JL.Negligible depletion solid-phase microextraction with radiolabeled analytes to study free concentrations and protein binding:an example with[3H] estradiol[J].Anal Chem, 2002;74:5993-7
9 Dockal M, Carter DC, Rǜker F.Conformational transitions of the three recombinant domains of human serum albumin depending on pH[J].J Biol Chem, 2000;275:3042-50
10 Dockal M, Carter DC, Rǜker F.The three recombinant domains of human serum albumin.Structural characterization and ligand binding properties[J].J Biol Chem, 1999;274:29303-10
11 Colmenarejo G.In silico prediction of drug-binding strengths to human serum albumin[J].Med Res Rev, 2003;23:275- 301
12 Sudlow G, Birkett DJ, Wade DN.The characterization of two specific drug binding sites on human serum albumin[J].Mol Pharmacol, 1975;11:824-32
13 Liu R, Pidikiti R, Ha C-E, Petersen CE, NV.The role of electrostatic interactions in human serum albumin binding and stabilization by halothane[J].J Biol Chem, 2002;277:36373-9
14 Kopecky Jr V, Ettrich R, Hofbauerova K, V Baumruk.Structure of human alpha1-acid gly coprotein and its high-affinity binding site[J].Biochem Biophys Res Commun, 2003;300: 41-6
15 Fournier T, Medjoubi NN, Porquet D.Alpha-1-acid glycoprotein[J].Biochim Biophy s Acta, 2000;1482:157-71
16 Nagy K, Vekey K, Imre T.Electrospray ionization fourier transform ion cyclotron resonance mass spectrometry of human alpha-1-acid gly coprotein[J].Anal Chem, 2004;76:4998- 5005
17 Israili ZH, Dayton PG.Human alpha-1-gly coprotein and its interactions with drugs[J].Drug Metab Rev, 2001;33:161- 235
18 Taheri S, Cogswell LP, Gent A, Strichartz GR.Hydrophobic and ionic factors in the binding of local anesthetics to the major variant of human 1-acid glycoprotein[J].J Pharmacol Exp Ther, 2003;304:71-80
19 Nishi K, Maruyama T, Halsall HB.Binding of alpha1-acid gly coprotein to membrane results in a unique structural change and ligand release[J].Biochemistry, 2004;43:10513-9
20 Fitos I, Visy J, Zsila F.Specific ligand binding on genetic variants of human alpha1-acid glycoprotein studied by circular dichroism spectroscopy[J].Biochem Pharmacol, 2004;67: 679-88
21 Lejon S, Frick IM, Björck L.Crystal structure and biological implications of a bacterial albumin binding module in complex with human serum albumin[J].J Biol Chem, 2004;279: 42924-8
22 Alvarez-Sanchez R, Divkovic M, Basketter D.Effect of glutathione on the covalent binding of the 13C-labeled skin sensitizer 5-chloro-2-methylisothiazol-3-one to human serum albumin: identification of adducts by nuclear magnetic resonance, matrixassisted laser desorption ionization mass spectrometry, and nanoelectrospray tandem mass spectrometry[J].Chem Res Toxicol, 2004;17:1280-8
23 Henrotte V, Laurent S, Gabelica V.Investigation of non-covalent interactions between paramagnetic complexes and human serum albumin by electrospray mass spectrometry[J].Rapid CommunMass Spectrom, 2004;18:1919-24
24 Lucas LH, Price KE, Larive CK.Epitope mapping and competitive binding of HSA drug site II ligands by NMR diffusion measurements[J].J Am Chem Soc, 2004;126:14258-66
25 Kitamura K, Kume M, Yamamoto M.19F NMR spectroscopic study on the binding of triflupromazine to bovine and human serum albumins[J].J Pharm Biomed Anal, 2004;36:411-4
26 Shikii K, Sakurai S, Utsumi H.Application of the 19F NMR technique to observe binding of the general anesthetic halothane to human serum albumin[J].Anal Sci, 2004;20:1475-7
27 Karney CFF, Ferrara JE, Brunner S.Method for computing protein binding affinity[J].J Comput Chem, 2004;26:243-51
28 Stanton DT, Mattioni BE, Knittel JJ, Jurs PC.Development and use of hydrophobic surface area (HSA)descriptors for computer- assisted quantitative structure-activity and structure-property relationship studies[J].J Chem Inf Comput Sci, 2004;44:1010-23
29 Lin JH, Lu A YH.Role of pharmacokinetics and metabolism in drug discovery and development[J].Pharmacol Rev, 1997;49:403-49
30 MacKichan JJ.Protein binding drug displacement interactions fact or fiction[J].Clin Pharmacokinet, 1989;16:65-73
31 Kurz H, Trunk H, Weitz B.Evaluation of methods to determine protein-binding of drugs.Equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration [J].Arzneimittelforschung, 1977;27:1373-80
32 Pacifici GM, Viani A.Methods of determining plasma and tissue binding of drugs.Pharmacokinetic consequences[J].Clin Pharmacokinet, 1992;23:449-68
33 Barre J, Chamouard JM, Houin G, Tillement JP.Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid[J].Clin Chem, 1985;31:60-4
34 Banker MJ, Clark TH, Williams JA.Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding[J].J Pharm Sci, 2003;92:967-74
35 Swart R, Koivisto P, Markides KE.Column switching in capillary liquid chromatography-tandem mass spectrometry for the quantitation of pg ml concentrations of the free basic drug tolterodine and its active 5-hydroxymethy l metabolite in microliter volumes of plasma[J].J Chromatogr A, 1998;828:209-18
36 Fung EN, Chen YH, Lau YY.Semi-automatic high-throughput determination of plasma protein binding using a 96-well plate filtrate assembly and fast liquid chromatography-tandem mass spectrometry[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2003;795:187-94
37 Goda R, Murayama N, Fujimaki Y, Sudo K.Simple and sensitive liquid chromatography-tandem mass spectrometry method for determination of the S(+)- and R(-)-enantiomers of baclofen in human plasma and cerebrospinal fluid[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2004;801:257-64
38 Zsila F, Bikadi Z, SimonyiM.Probing the binding of the flavonoid, quercetin to human serum albumin by circular dichroism, electronic absorption spectroscopy and molecular modelling methods[J].Biochem Pharmacol, 2003;65:447-56
39 Zhang S, Van Pelt CK, Wilson DB.Quantitative determination of noncovalent binding interactions using automated nanoelectrospray mass spectrometry[J].Anal Chem, 2003;75:3010-8
40 Tjernberg A, Carno S, Oliv F.Determination of dissociation constants for protein-ligand complexes by electrospray ionization mass spectrometry[J].Anal Chem, 2004;76:4325-31
41 Tian J, Liu J, He W.Probing the binding of scutellarin to human serum albumin by circular dichroism, fluorescence spectroscopy, FTIR, and molecular modeling method[J].Biomacromolecules, 2004;5:1956-61
42 Trynda-Lemiesz L, Luczkowski M.Human serum albumin: spectroscopic studies of the paclitaxel binding and proximity relationships with cisplatin and adriamycin[J].J Inorg Biochem, 2004;98:1851-6
43 Fabriciova G, Sanchez-Cortes S, Garcia-Ramos JV, Miskovsky P.Surface-enhanced Raman spectroscopy study of the interaction of the antitumoral drug emodin with human serum albumin [J].Biopolymers, 2004;74:125-30
44 Shibukawa A, Nakagawa T.Theoretical Study of High-performance frontal analysis:a chromatographic method for determination of drug-protein interaction[J].Anal Chem, 1996;68: 447-54
45 Chen J, Ohnmacht C, Hage DS.Studies of phenytoin binding to human serum albumin by high-performance affinity chromatography[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2004;809:137-45
46 Ostergaard J, Schou C, Larsen C, Heegaard NH.Effect of dextran as a run buffer additive in drug-protein binding studies using capillary electrophoresis frontal analysis[J].Anal Chem, 2003;75:207-14
47 Martinez-Pla JJ, Martinez-GomezMA, Martin-Biosca Y.Highthroughput capillary electrophoresis frontal analysis method for the study of drug interactions with human serum albumin at near-physiological conditions[J].Electrophoresis, 2004;25: 3176-85
48 Zhao X, You T, Liu J.Drug-human serum albumin binding studied by capillary electrophoresis with electrochemiluminescence detection[J].Electrophoresis, 2004;25:3422-6
49 Tsai TH.Assaying protein unbound drugs using microdialysis techniques[J].J Chromatogr B Analyt Technol Biomed Life Sci, 2003;797:161-73
50 Tsai TH, LiuMC.Determination of unbound theophylline in rat blood and brain by microdialy sis and liquid chromatography[J]. J Chromatogr A, 2004;1032:97-101
51 Hartrick CT, Dirkes WE, Coyle DE.Influence of bupivacaine on mepivacaine protein binding [J].Clin Pharmacol Ther, 1984;36:546-50
52 Chuang VT, Otagiri M.How do fatty acids cause allosteric binding of drugs to human serum albumin[J].Pharm Res, 2002;19:1458-64
53 De Rick AF, Belpaire FM, Dello C, BogaertMG.Influence of enhanced alpha-1-acid gly coprotein concentration on protein binding, pharmacokinetics and antiarrhythmic effect of lidocaine in the dog[J].J Pharmacol Exp Ther, 1987;241:289-93
54 Yoo SD, Holladay JW, Fincher TK.Altered disposition and antidepressant activity of imipramine in transgenic mice with elevated alpha-1-acid glycoprotein[J].J Pharmacol Exp Ther, 1996;276:918-22
55 Routledge PA, Kitchell BB, Bjornsson TD.Diazepam and Ndesmethyldiazepam redistribution after heparin[J].Clin Pharmacol Ther, 1980;27:528-32
56 Wong BK, Bruhin PJ, Barrish A, Lin JH.Nonlinear dorzolamide pharmacokinetics in rats:concentration-dependent erythrocyte distribution and drug-metabolite displacement interaction [J].Drug Metab Dispos, 1996;24:659-63
57 Pahlman I, Gozzi P.Serum protein binding of tolterodine and its major metabolites in humans and several animal species[J]. Biopharm Drug Dispos, 1999;20:91-9
58 Machinist JM, Kukulka MJ, Bopp BA.In vitro plasma protein binding of zileuton and its N-dehydroxylated metabolite[J]. Clin Pharmacokinet, 1995;29:34-41
59 Wilkinson GR.Plasma and tissue binding considerations in drug disposition[J].Drug Metab Rev, 1983;14:427-65
60 Talbert AM, Tranter GE, Holmes E, Francis PL.Determination of drug-plasma protein binding kinetics and equilibria by chromatographic profiling:exemplification of the method using L-tryptophan and albumin[J].Anal Chem, 2002;74:446-52
61 Harada D, Naito S, Otagiri M.Kinetic analysis of covalent binding between N-acetyl-L-cysteine and albumin through the formation of mixed disulfides in human and rat serum in vitro [J].Pharm Res, 2002;19:1648-54
62 Timerbaev AR, Aleksenko SS, Polec-Pawlak K.Platinum metallodrug- protein binding studies by capillary electrophoresis-inductively coupled plasma-mass spectrometry:characterization of interactions between Pt(II)complexes and human serum albumin[J].Electrophoresis, 2004;25:1988-95
63 Weisiger RA.Dissociation from albumin:a potentially rate-limiting step in the clearance of substances by the liver[J].PNAS, 1985;82:1563-7
64 Fuse E, Hashimoto A, Sato N.Phy siological modeling of altered pharmacokinetics of a novel anticancer drug, UCN-01 (7- hydroxystaurosporine), caused by slow dissociation of UCN-01 from human alpha 1-acid gly coprotein[J].Pharm Res, 2000;17:553-64
65 Ohkawa T, Norikura R, Yoshikawa T.Rapid LC-TOFMS method for identification of binding sites of covalent acylglucuronide- albumin complexes[J].J Pharm Biomed Anal, 2003;31:1167-76
66 Harada D, Anraku M, Fukuda H.Kinetic studies of covalent binding between N-acety l-L-cysteine and human serum albumin through a mixed-disulfide using an N-methy lpy ridinium polymer- based column[J].Drug Metab Pharmacokinet, 2004;19: 297-302
67 Bertucci C, Domenici E.Reversible and covalent binding of drugs to human serum albumin:methodological approaches and physiological relevance[J].Curr Med Chem, 2002;9:1463-81
68 Levy RH, Moreland TA.Rationale for monitoring free drug levels[J].Clin Pharmacokinet, 1984;9:1-9
69 Greenblatt DJ, Sellers EM, Koch-Weser J.Importance of protein binding for the interpretation of serum or plasma drug concentrations[J].J Clin Pharmacol, 1982;22:259-63
70 MacKichan JJ.Pharmacokinetic consequences of drug displacement from blood and tissue proteins[J].Clin Pharmacokinet, 1984;9:32-41
71 Wilkinson GR.Clearance approaches in pharmacology [J]. Pharmacol Rev, 1987;39:1-47
72 Martin BK.Kinetics of elimination of drugs possessing high affinity for the plasma proteins[J].Nature, 1965;207:959-60
73 Branch RA, James J, Read AE.A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)-propranolol[J].Br J Clin Pharmacol, 1976;3:243-9
74 RowlandM.Protein binding and drug clearance[J].Clin Pharmacokinet, 1984;9:10-7
75 Benet LZ, Hoener BA.Changes in plasma protein binding have little clinical relevance[J].Clin Pharmacol Ther, 2002;71: 115-21
76 Rolan PE.Plasma protein binding displacement interactions-- why are they still regarded as clinically important[J].Br J Clin Pharmacol, 1994;37:125-8
77 Ito K, Iwatsubo T, Kanamitsu S.Prediction of pharmacokinetic alterations caused by drug-drug interactions:metabolic interaction in the liver[J].Pharmacol Rev, 1998;50:387-412
78 du Souich P, Verges J, Erill S.Plasma protein binding and pharmacological response[J].Clin Pharmacokinet, 1993;24: 435-40
79 Lam YW, Duroux MH, Gambertoglio JG.Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers[J].Antimicrob Agents Chemother, 1988;32:298-302
80 Yoo SD, Holladay JW, Fincher TK.Altered disposition and antidepressant activity of imipramine in transgenic mice with elevated alpha-1-acid glycoprotein[J].J Pharmacol Exp Ther, 1996;276:918-22
81 De Rick AF, Belpaire FM, Dello C, BogaertMG.Influence of enhanced alpha-1-acid gly coprotein concentration on protein binding, pharmacokinetics and antiarrhythmic effect of lidocaine in the dog[J].J Pharmacol Exp Ther, 1987;241:289-93
82 Weber LT, ShipkovaM, Armstrong VW.The pharmacokineticpharmacodynamic relationship for total and free mycophenolic acid in pediatric renal transplant recipients:a report of the German study group on mycophenolate mofetil therapy[J].J Am Soc Nephrol, 2002;13:759-68
83 Yasuhara M, Fujiwara J, Kitade S.Effect of altered plasma protein binding on pharmacokinetics and pharmacodynamics of propranolol in rats after surgery:role of alpha-1- acid glycoprotein[J].J Pharmacol Exp Ther, 1985;235:513-20
84 Anton AH.The relation between the binding of sulfonamides to albumin and their antibacterial efficacy[J].J Pharmacol Exp Ther, 1960;129:282-90
85 Krǜger EA, Figg WD.Protein binding alters the activity of suramin, carboxyamidotriazole, and UCN-01 in an ex vivo rat aortic ring angiogenesis assay[J].Clin Cancer Res, 2001;7: 1867-72
86 Holford NH, Sheiner LB.Understanding the dose-effect relationship: clinical application of pharmacokinetic- pharmacodynamic models[J].Clin Pharmacokinet, 1981;6:429-53
87 QinM, Nilsson M, Oie S.Decreased elimination of drug in the presence of alpha-1-acid glycoprotein is related to a reduced hepatocyte uptake [J].J Pharmacol Exp Ther, 1994;269: 1176-81
88 Riant P, Urien S, Albengres E.Effects of the binding of imipramine to erythrocytes and plasma proteins on its transport through the rat blood-brain barrier[J].J Neurochem, 1988;51:421-5
89 Weisiger R, Gollan J, Ockner R.Receptor for albumin on the liver cell surface may mediate uptake of fatty acids and other albumin- bound substances[J].Science, 1981;211:1048-51
90 Reed RG, Burrington CM.The albumin receptor effect may be due to a surface-induced conformational change in albumin[J]. J Biol Chem, 1989;264:9867-72
91 De Wolf FA, Brett GM.Ligand-binding proteins:their potential for application in systems for controlled delivery and uptake of ligands[J].Pharmacol Rev, 2000;52:207-36
92 Weisiger RA, Zucker SD.Transfer of fatty acids between intracellular membranes:roles of soluble binding proteins, distance, and time[J].Am J Physiol Gastrointest Liver Physiol, 2002; 282:105-15

[1]	李坤, 李璐璐, 李楠楠, 胡卫红, 周建超. 成人肾移植术后血糖控制和CYP3A5基因多态性对他克莫司谷浓度的影响[J]. 中国临床药理学与治疗学, 2023, 28(7): 767-774.
[2]	张远金, 黄盛博, 刘洁, 王昕. 药物代谢创新模型：基因编辑大鼠和小肠3D类器官[J]. 中国临床药理学与治疗学, 2021, 26(8): 914-922.
[3]	徐国防, 高盼, 刘平, 张孝磊, 荆萃, 张翠翠, 荆会霞, 李晓苏, 齐琦. 卡培他滨片在肿瘤患者中的生物等效性研究[J]. 中国临床药理学与治疗学, 2020, 25(10): 1119-1124.
[4]	王小青，周杰兆，程泽能，姜德建. 失重环境药物代谢动力学研究[J]. 中国临床药理学与治疗学, 2017, 22(6): 709-712.
[5]	王瑜，仲云熙，金孝亮，谷世寅，彭英，尹莉芳，贾元威，孙建国，王广基. 高效液相色谱-串联质谱法测定犬血浆中的普瑞巴林及在药代动力学中的应用[J]. 中国临床药理学与治疗学, 2016, 21(7): 731-738.
[6]	朱胤慈, 孙建国, 彭英, 王广基. 前药的药代动力学研究进展[J]. 中国临床药理学与治疗学, 2012, 17(12): 1433-1440.
[7]	钟杰, 王海南, 马越鸣. 中药药物代谢动力学在中药新药研究中的作用[J]. 中国临床药理学与治疗学, 2010, 15(3): 241-246.
[8]	王文萍, 曹琦琛, 王华伟, 吕玉萍. 当归补血汤不同配伍的药动学研究[J]. 中国临床药理学与治疗学, 2009, 14(6): 659-663.
[9]	汪音, 杨劲, 傅继华, 刘晓东, 王广基. 基于体外模型数据模拟和预测人体内群体药代参数[J]. 中国临床药理学与治疗学, 2008, 13(5): 545-551.
[10]	黄敏文, 王广基, 李昊, 孙建国. HPLC-MS/MS 法同时测定Beagle 犬血浆中槲皮素、山萘酚和异鼠李素[J]. 中国临床药理学与治疗学, 2008, 13(12): 1330-1338.
[11]	汪长生, 刘晓平, 马张庆, 宋建国. 不同剂量丙磺舒对头孢克罗药物动力学的影响[J]. 中国临床药理学与治疗学, 2002, 7(2): 130-133.
[12]	孙成春, 赵小元, 曹洋, 王景祥. 克拉霉素对兔体内稳态时氨茶碱药代动力学的影响[J]. 中国临床药理学与治疗学, 2002, 7(1): 21-23.
[13]	刘军保, 陈小川, 曹崎, 杨广德, 杨银京. 阿斯咪唑混悬剂的人体药代动力学[J]. 中国临床药理学与治疗学, 1998, 3(3): 187-189.
[14]	刘军保, 陈小川, 曹崎, 杨广德, 杨银京. 阿斯咪唑片剂人体药代动力学和生物利用度的初步研究[J]. 中国临床药理学与治疗学, 1998, 3(2): 124-126.