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Protein Binding of Anticancer Drugs

  • Chapter
Handbook of Anticancer Pharmacokinetics and Pharmacodynamics

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

During the last few decades, the value to clinical practice of determining plasma concentrations of chemotherapeutic agents has been demonstrated convincingly for several important drugs (1). Such tests generally are not appropriate for drugs of limited effectiveness and potency and in patients who respond well to the usual dosage regimen of a drug. They are also superfluous for drugs whose intensity of action can be judged accurately during their clinical use and whose dosage can be adjusted on that basis. Nevertheless, a broad area of clinical usefulness remains. Measurement of plasma concentrations generally clarifies the picture when usual doses of a drug fail to produce therapeutic benefits or result in unexpected toxicity. It has been proven particularly helpful in patients with hepatic or renal function disorders in whom the relationship between dosage and plasma concentration may be grossly abnormal, or when drugs are being administered concomitantly and may be altering each other’s metabolic fate (2,3). Clearly, determinations of drug concentrations in plasma will become more widely applicable as we expand our knowledge of the pharmacologic correlates of plasma levels to clinical outcome for more drugs. One problem in achieving individual dose adjustment is identifying and interpreting what constitutes the therapeutic concentration of a drug in plasma. The intensity of effect is usually related to the concentration of the drug in the plasma water phase, as this establishes the diffusion gradient for the drug to reach its site of action (4). The relationships of drug-plasma protein binding to the process that establishes the concentration of drug at the active site are shown in Fig. 1. Surprisingly, only in a few instances, plasma protein binding can significantly affect pharmacokinetic processes, such as distribution and elimination by renal and/or hepatic mechanisms, and thus have important pharmacodynamic implications (5). Here, we discuss (1) the methodological aspects of protein-ligand interactions, (2) the relationship between protein binding and drug disposition, and (3) the clinical relevance of free drug monitoring in cancer patients.

“Dismiss the idea that protein binding is a major influence of elimination.”

—SH Curry, “Drug Disposition and Metabolism,” Blackwell, Oxford, 1980

“Changes in plasma protein binding have little clinical relevance.”

—LZ Benet, BA Hoener. Clin Pharmacol Ther 2002; 71:115–121

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References

  1. Van den Bongerd HJ, Mathot RA, Beijnen JH, Schellens JHM. Pharmacokinetically guided administration of chemotherapeutic agents. Clin Pharmacokinet 2000; 39: 345–367.

    Google Scholar 

  2. Kintzel PE, Dorr RT. Anticancer drug renal toxicity and elimination: dosing guidelines for altered renal function. Cancer Treat Rev 1995; 21: 33–64.

    Article  PubMed  CAS  Google Scholar 

  3. Donelli MG, Zucchetti M, Munzone E, D’Incalci M, Crosignani A. Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer 1998; 34: 33–46.

    Article  PubMed  CAS  Google Scholar 

  4. Rowland M, Tozer TN. Clinical pharmacokinetics; concepts and applications. Philadelphia, PA: Lea and Febiger, 1989.

    Google Scholar 

  5. Rowland M. Protein binding and drug clearance. Clin Pharmacokinet 1984; 9: 10–17.

    Article  PubMed  CAS  Google Scholar 

  6. Monot C, Lapicque F, Benamghar L, Muller N, Payan E, Netter P. Representation of affinity in the case of co-operativity in protein-ligand binding. Fundam Clin Pharmacol 1994; 8: 18–25.

    Article  PubMed  CAS  Google Scholar 

  7. Pedersen JB, Lindup WE. Interpretation and analysis of receptor binding experiments which yield nonlinear Scatchard plots and binding constants dependent upon receptor concentration. Biochem Pharmacol 1994; 47: 179–185.

    Google Scholar 

  8. Klotz IM. Numbers of receptor sites from Scatchard graphs: facts and fantasies. Science 1982; 217: 1247–1249.

    Article  PubMed  CAS  Google Scholar 

  9. Munson PJ, Rodbard D. Number of receptor sites from Scatchard and Klotz graphs: a constructive critique. Science 1983 220: 979–981.

    Article  PubMed  CAS  Google Scholar 

  10. Zierler K. Misuse of nonlinear Scatchard plots. Trends Biochem Sci 1989; 14: 314–317.

    Article  PubMed  CAS  Google Scholar 

  11. Kermode JC. The curvilinear Scatchard plot. Experimental artifact or receptor heterogeneity? Biochem Pharmacol 1989; 38: 2053–2060.

    Article  PubMed  CAS  Google Scholar 

  12. Klotz IM. Physiochemical aspects of drug—protein interactions: a general perspective. Ann NY Acad Sci 1973; 226: 18–35.

    Article  PubMed  CAS  Google Scholar 

  13. Oravcovd J, Böhs B, Lindner W. Drug-protein binding studies. New trends in analytical and experimental methodology. J Chromatogr B 1996; 677: 1–28.

    Article  Google Scholar 

  14. Kurz H, Trunk H, Weitz B. Evaluation of methods to determine protein-binding of drugs. Equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration. Arzneimittelforsch 1997; 27: 1373–1380.

    Google Scholar 

  15. Bowers WF, Fulton S, Thompson J. Ultrafiltration vs equilibrium dialysis for determination of free fraction. Clin Pharmacokinet 1984; S 1: 49–60.

    Google Scholar 

  16. Huang JD. Errors in estimating the unbound fraction of drugs due to the volume shift in equilibrium dialysis. J Pharmaceut Sci 1983; 72: 1368–1369.

    Article  CAS  Google Scholar 

  17. Mapleson WW. Computation of the effect of Donnan equilibrium on pH in equilibrium dialysis. J Pharmacol Methods 1987; 17: 231–242.

    Article  PubMed  CAS  Google Scholar 

  18. Reinard T, Jacobsen HJ. An inexpensive small volume equilibrium dialysis system for protein-ligand binding assays. Analyt Biochem 1989; 176: 157–160.

    Article  PubMed  CAS  Google Scholar 

  19. Parsons DL, Fan HF. Loss of propranolol during ultrafiltration in plasma protein binding studies. Res Commun Chem Pathol Pharmacol 1986; 54: 405–408.

    PubMed  CAS  Google Scholar 

  20. Oellerich M, Mnuller-Vahl H. The EMIT FreeLevel ultrafiltration technique compared with equilibrium dialysis and ultracentrifugation to determine protein binding of phenytoin. Clin Pharmacokinet 1984; S 1: 61–70.

    Google Scholar 

  21. Verbeeck RK, Cardinal JA. Plasma protein binding of salicylic acid, phenytoin, chlorpromazine, propranolol and pethidine using equilibrium dialysis and ultracentrifugation. Arzneimittelforsch 1985; 35: 903–906.

    PubMed  CAS  Google Scholar 

  22. Bane J, Chamouard JM, Houin G, Tillement JP. Equilibrium dialysis, ultrafiltration, and ultracentrifugation compared for determining the plasma-protein-binding characteristics of valproic acid. Clin Chem 1985; 31: 60–64.

    Google Scholar 

  23. Hage DS. High-performance affinity chromatography: a powerful tool for studying serum protein binding. J Chromatogr B 2002; 768: 3–30.

    Article  CAS  Google Scholar 

  24. Garcia Alvarez-Coque MC, Carda Broch S. Direct injection of physiological fluids in micellar liquid chromatography. J Chromatogr B 1999; 736: 1–18.

    Article  CAS  Google Scholar 

  25. Heegaard NH. Capillary electrophoresis for the study of affinity interactions. J Mol Recogn 1998; 11: 141–148.

    Article  CAS  Google Scholar 

  26. Hage DS, Tweed SA. Recent advances in chromatographic and electrophoretic methods for the study of drug-protein interactions. J Chromatogr B 1997; 699: 499–525.

    Article  CAS  Google Scholar 

  27. Gomez FA, Avila LZ, Chu YH, Whitesides GM. Determination of binding constants of ligands to proteins by affinity capillary electrophoresis: compensation for electroosmotic flow. Analyt Chem 1994; 66: 1785–1791.

    Article  CAS  Google Scholar 

  28. Sugiyama Y, Suzuki Y, Sawada Y, et al. Auramine O as a fluorescent probe for the binding of basis drugs to human alpha 1-acid glycoprotein (alpha 1-AG). The development of simple fluorometric method for the determination of alpha 1-AG in human serum. Biochem Pharmacol 1985; 34: 821–829.

    Article  PubMed  CAS  Google Scholar 

  29. Rahman MH, Maruyama T, Okada T, Yamasaki K, Otagiri M. Study of interaction of carprofen and its enantiomers with human serum albumin I. Mechanism of binding studied by dialysis and spectro- scopic methods. Biochem Pharmacol 1993; 46: 1721–1731.

    Article  PubMed  CAS  Google Scholar 

  30. Morin D, Zini R, Ledewyn S, Tillement JP. Inhibition of binedaline binding to human alpha 1-acid glycoprotein and other serum proteins by chlorpromazine, imipramine, and propranolol. J Pharmaceut Sci 1986; 75: 883–885.

    Article  CAS  Google Scholar 

  31. Chen A, Shapiro MJ. Affinity NMR. Analyt Chem 1999; 71:669A–675A.

    Google Scholar 

  32. Chignell CF. Optical studies of drug-protein complexes. II. Interaction of phenylbutazone and its analogues with human serum albumin. Mol Pharmacol 1969; 5: 244–252.

    PubMed  CAS  Google Scholar 

  33. Chignell CF. Optical studies of drug-protein complexes. 3. Interaction of flufenamic acid and other Narylanthranilates with serum albumin. Mol Pharmacol 1969; 5: 455–462.

    PubMed  CAS  Google Scholar 

  34. Chignell CF, Starkwheather DK. Optical studies of drug-protein complexes. V. The interaction of phenylbutazone, flufenamic acid, and dicoumarol with acetylsalicylic acid-treated human serum albumin. Mol Pharmacol 1971; 7: 229–237.

    PubMed  CAS  Google Scholar 

  35. Squella JA, Becerra R, Nunez-Vergara LJ. Polarography: a new toll in the elucidation of drug-albumin interactions. Biochem Pharmacol 1987; 36: 3531–3533.

    Article  PubMed  CAS  Google Scholar 

  36. Ali H, Yamamoto M. Thermodynamics of the binding of phenothiazines to human plasma, human serum albumin and alpha 1-acid glycoprotein: a calorimetric study. J Pharmaceut Pharmacol 1989; 41: 674–679.

    Article  Google Scholar 

  37. Shaklai N, Garlick RL, Bunn HF. Nonenzymatic glycosylation of human serum albumin alters its conformation and function. J Biol Chem 1984; 259: 3812–3817.

    PubMed  CAS  Google Scholar 

  38. Chen BH, Taylor EH, Pappas AA. Total and free dispyramide by fluorescence polarization immunoassay and relationship between free fraction and alpha-1 acid glycoprotein. Clin Chim Acta 1987; 163: 75–80.

    Article  PubMed  CAS  Google Scholar 

  39. Nelson RW, Krone JR. Advances in surface plasmon resonance biomolecular interaction analysis mass spectrometry (BIA/MS). J Mol Recogn 1999; 12: 77–93.

    Article  CAS  Google Scholar 

  40. Sablonniere B, Dallery N, Griller I, Formstecher P, Dautrevaux M. Physicochemical parameters affecting the charcoal adsorption assay for quantitative retinoid-binding measurement. Analyt Biochem 1994; 217: 110–118.

    Article  PubMed  CAS  Google Scholar 

  41. Yuan J, Yang DC, Birkmeier J, Stolzenbach J. Determination of protein binding by in vitro charcoal adsorption. J Pharmacokinet Biopharmacol 1995; 23: 41–55.

    Article  CAS  Google Scholar 

  42. Svensson CK, Woodruff MN, Baxter JG, Lalka D. Free drug concentration monitoring in clinical practice. Rationale and current status. Clin Pharmacokinet 1986; 11: 450–469.

    Article  PubMed  CAS  Google Scholar 

  43. Drobitch RK, Svensson CK. Therapeutic drug monitoring in saliva. An update. Clin Pharmacokinet 1992; 23: 365–379.

    Article  PubMed  CAS  Google Scholar 

  44. Highley MS, de Bruijn EA. Erythrocytes and the transport of drugs and endogenous compounds. Pharmaceut Res 1996; 13: 186–195.

    Article  CAS  Google Scholar 

  45. Hinderling PH. Red blood cells: a neglected compartment in pharmacokinetics and pharmacodynamics. Pharmacol Rev 1997; 49: 279–295.

    PubMed  CAS  Google Scholar 

  46. Linhares MC, Kissinger PT. Capillary ultrafiltration: in vivo sampling probes for small molecules. Analyt Chem 1992; 64: 2831–2835.

    Article  CAS  Google Scholar 

  47. Scott DO, Sorenson LR, Steele KL, Punckett DL, Lunte CE. In vivo microdialysis sampling for pharmacokinetic investigations. Pharmaceut Res 1991; 8: 389–392.

    Article  CAS  Google Scholar 

  48. Muller M. Science, medicine, and the future: microdialysis. Br Med J 2002; 324: 588–591.

    Article  Google Scholar 

  49. Wilkinson GR. Plasma and tissue binding considerations in drug disposition. Drug Metab Rev 1985; 151: 193–203.

    Google Scholar 

  50. Meijer DKF, Van der Sluijs P. Covalent and noncovalent binding of drugs: implications for hepatic clearance, storage, and cell-specific drug delivery. Pharmaceut Res 1989; 6: 105–118.

    Article  CAS  Google Scholar 

  51. Stewart CF, Zamboni WC. Plasma protein binding of chemotherapeutic agents. In: Grochow LB, Ames MM (eds). A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics. Baltimore, MD: Williams and Williams, 1998, pp. 55–66.

    Google Scholar 

  52. Wagner JG. Fundamentals of Clinical Pharmacokinetics. Hamilton, IL: Drug Intelligence Publications, 1979.

    Google Scholar 

  53. Lind MJ, Ardiet C. Pharmacokinetics of alkylating agents. Cancer Sury 1993; 17: 157–188.

    CAS  Google Scholar 

  54. Reidenberg MM, Odar-Ceederlof I, von Bahr C, Borga O, Sjoqvist F. Protein binding of diphenylhydantoin and demethylimipramide in plasma from patients with poor renal function. N Engl J Med 1971; 285: 264–267.

    Article  PubMed  CAS  Google Scholar 

  55. Kragh-Hansen U. Structure and ligand binding properties of human serum albumin. Dan Med Bull 1990; 37: 57–84.

    PubMed  CAS  Google Scholar 

  56. Grandison MK, Boudinot FD. Age-related changes in protein binding of drugs: implications for therapy. Clin Pharmacokinet 2000; 38: 271–290.

    Article  PubMed  CAS  Google Scholar 

  57. Fremstad D, Bergerud K, Haffner JF, Lunde PK. Increased plasma binding of quinidine after surgery: a preliminary report. Eur J Clin Pharmacol 1976; 10: 441–444.

    Article  PubMed  CAS  Google Scholar 

  58. Zini R, Riant P, Barre J, Tillement JP. Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part I). Clin Pharmacokinet 1990; 19: 147–159.

    Article  PubMed  CAS  Google Scholar 

  59. Zini R, Riant P, Barre J, Tillement JP. Disease-induced variations in plasma protein levels. Implications for drug dosage regimens (Part II). Clin Pharmacokinet 1990; 19: 218–229.

    Article  PubMed  CAS  Google Scholar 

  60. Bacchus H. Serum glycoproteins and malignant neoplastic diseases. Prog Clin Pathol 1977; 6: 111–135.

    Google Scholar 

  61. Bacchus H. Serum glycoproteins in cancer. Prog Clin Pathol 1975; 6: 111–135.

    PubMed  CAS  Google Scholar 

  62. Rossing N. Albumin metabolism in neoplastic diseases. Scand J Clin Lab Invest 1968; 22: 211–216.

    Article  PubMed  CAS  Google Scholar 

  63. MacKichan JJ. Influence of protein binding and use of unbound (free) drug concentrations. In: Evans WE, Shentag JJ, Jusko WJ (eds). Applied Pharmacokinetics: Principles and Therapeutic Drug Monitoring. Vancouver, Canada: Applied Therapeutics, 1992, pp. 1–48.

    Google Scholar 

  64. Rudman D, Treadwell PE, Vogler WR, et al. An abnormal orosomucoid in the plasma of patients with neoplastic disease. Cancer Res 1972; 32: 1951–1952.

    PubMed  CAS  Google Scholar 

  65. Wallace SM, Verbeeck RK. Plasma protein binding in the elderly. Clin Pharmacokinet 1987; 12: 41–72.

    Article  PubMed  CAS  Google Scholar 

  66. Tinguely D, Baumann P, Conti M, Jonzier-Perey M, Schopf J. Interindividual differences in the binding of antidepressives to plasma proteins: the role of the variants of alpha 1-acid glycoprotein. Eur J Clin Pharmacol 1985; 27: 661–666.

    Article  PubMed  CAS  Google Scholar 

  67. Li JH, Xu, JQ, Cao XM, Ni L, Li Y, Zhuang YY, Gong JB. Influence of the ORM1 phenotypes on serum unbound concentration and protein binding of quinidine. Clin Chim Acta 2002; 317: 85–92.

    Article  PubMed  CAS  Google Scholar 

  68. Yost RL, DeVane CL. Diurnal variation of alpha 1-acid glycoprotein concentration in normal volunteers. J Pharmaceut Sci 1985; 74: 777–779.

    Article  CAS  Google Scholar 

  69. Van Breemen RB, Fenselau C, Mogilevsky W, Odell GB. Reaction of bilirubin glucuronides with serum albumin. J Chromatogr 1986; 383: 387–392.

    Article  PubMed  Google Scholar 

  70. Tozer TN. Concepts basic to pharmacokinetics. Pharmacol Ther 1981; 12: 109–1311.

    Article  PubMed  CAS  Google Scholar 

  71. Takahashi N, Takahashi Y, Isobe T, et al Amino acid substitutions in inherited albumin variants from Amerindian and Japanese populations. Proc Natl Acad Sci USA 1987; 84: 8001–8005.

    Article  PubMed  CAS  Google Scholar 

  72. Arai K, Ishioka N, Huss K, Madison J, Putnam FW. Identical structural changes in inherited albumin variants from different populations. Proc Natl Acad Sci USA 1989; 86: 434–438.

    Article  PubMed  CAS  Google Scholar 

  73. Galliano M, Minchiotti L, Porta F, et al. Mutations in genetic variants of human serum albumin found in Italy. Proc Natl Acad Sci USA 1990; 87: 8721–8725.

    Article  PubMed  CAS  Google Scholar 

  74. Reed RG. Ligand-binding properties of albumin Parklands: Asp365 His. Biochim Biophys Acta 1988; 965: 114–117.

    Article  CAS  Google Scholar 

  75. Vestberg K, Galliano M, Minchiotti L, Kragh-Hansen U. High-affinity binding of warfarin, salicylate and diazepam to natural mutants of human serum albumin modified in the C-terminal end. Biochem Pharmacol 1992; 44: 1515–1521.

    Article  PubMed  CAS  Google Scholar 

  76. Paxton JW, Jurlina JL, Foote SE. The binding of amsacrine to human plasma proteins. J Pharmaceut Pharmacol 1986; 38: 432–438.

    Article  CAS  Google Scholar 

  77. Crooke ST, Luft F, Broughton A, Strong J, Casson K, Einhorn L. Bleomycin serum pharmacokinetics as determined by a radioimmunoassay and a microbiologic assay in a patient with compromised renal function. Cancer 1977; 39: 1430–1434.

    Article  PubMed  CAS  Google Scholar 

  78. King SY, Agra AM, Shen HS, et al. Protein binding of brequinar in the plasma of healthy donors and cancer patients and analysis of the relationship between protein binding and pharmacokinetics in cancer patients. Cancer Chemother Pharmacol 1994; 35: 101–108.

    Article  PubMed  CAS  Google Scholar 

  79. Ehrsson H, Hassan M. Binding of busulfan to plasma proteins and blood cells. J Pharmaceut Pharmacol 1984; 36: 694–696.

    Article  CAS  Google Scholar 

  80. Go RS, Adjei AA. Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17: 409–422.

    PubMed  CAS  Google Scholar 

  81. Newell DR, Calvert AH, Harrap KR, McElwain TJ. Studies on the pharmacokinetics of chlorambucil and prednimustine in man. Br J Clin Pharmacol 1983; 15: 253–258.

    Article  PubMed  CAS  Google Scholar 

  82. Ivanov AI, Chrostodoulou J, Parkinson JA, et al. Cisplatin binding sites on human albumin. J Biol Chem 1998; 273:14, 721–14, 730.

    Google Scholar 

  83. Boddy AV, Yule SM. Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 2000; 38: 291–304.

    Article  PubMed  CAS  Google Scholar 

  84. Van Prooijen HC, Vierwinden G, Wessels J, Haanen C. Cytosine arabinoside binding to human plasma proteins. Arch Int Pharmacodyn Ther 1977; 229: 199–205.

    Google Scholar 

  85. Slevin ML, Johnston A, Woollard RC, Piall EM, Lister TA, Turner P. Relationship between protein binding and extravascular drug concentrations of a water-soluble drug, cytosine arabinoside. J R Soc Med 1983; 76: 365–368.

    PubMed  CAS  Google Scholar 

  86. Urien S, Barré J, Morin C, Paccaly A, Montay G, Tillement JP. Docetaxel serum protein binding with high affinity to alphas-acid glycoprotein. Invest New Drugs 1996; 14: 147–151.

    Article  PubMed  CAS  Google Scholar 

  87. Eksborg S, Ehrsson H, Ekqvist B. Protein binding of anthraquinone glycosides, with special reference to adriamycin. Cancer Chemother Pharmacol 1982; 10: 7–10.

    Article  PubMed  CAS  Google Scholar 

  88. Demant EJ, Friche E. Equilibrium binding of anthracycline cytostatics to serum albumin and small unilamellar phospholipid vesicles as measured by gel filtration. Biochem Pharmacol 1998; 55: 27–32.

    Article  PubMed  CAS  Google Scholar 

  89. Stewart CF, Pieper JA, Arbuck SG, Evans WE. Altered protein binding of etoposide in patients with cancer. Clin Pharmacol Ther 1989; 45: 49–55.

    Article  PubMed  CAS  Google Scholar 

  90. Czejka M, Schuller J. [The binding of 5-fluorouracil to serum protein fractions, erythrocytes and ghosts under in vitro conditions]. Arch Pharm (Wienheim) 1992; 325: 69–71.

    Article  CAS  Google Scholar 

  91. Zheng JJ, Chan KK, Muggia F. Preclinical pharmacokinetics and stability of isophosphoramide mustard. Cancer Chemother Pharmacol 1994; 33: 391–398.

    Article  PubMed  CAS  Google Scholar 

  92. Combes O, Barré J, Duche JC, et al. In vitro binding and partitioning of irinotecan (CPT-11) and its metabolite, SN-38, in human blood. Invest New Drugs 2000; 18: 1–5.

    Article  PubMed  CAS  Google Scholar 

  93. Reece PA, Hill HS, Green RM, et al. Renal clearance and protein binding of melphalan in patients with cancer. Cancer Chemother Pharmacol 1988; 22: 348–352.

    Article  PubMed  CAS  Google Scholar 

  94. Gera S, Musch E, Osterheld HK, Loos U. Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma. Cancer Chemother Pharmacol 1989; 23: 76–80.

    Article  PubMed  CAS  Google Scholar 

  95. Sjoholm I, Stjerna B. Binding of drugs to human serum albumin XVII: irreversible binding of mercaptopurine to human serum proteins. J Pharmaceut Sci 1981; 70: 1290–1291.

    Article  CAS  Google Scholar 

  96. Maia MB, Saivin S, Chatelut E, Malmary MF, Houin G. In vitro and in vivo protein binding of methotrexate assessed by microdialysis. Int J Clin Pharmacol Ther 1996; 34: 335–341.

    PubMed  CAS  Google Scholar 

  97. Skibinska L, Ramlau C, Zaluski J, Olejniczak B. Methotrexate binding to human plasma proteins. Pol J Pharmacol Pharmaceut 1990; 42: 151–157.

    Article  CAS  Google Scholar 

  98. Graham MA, Lockwood GF, Greenslade D, Brienza S, Baysaas M, Gamelin E. Clinical pharmacokinetics of oxaliplatin: a critical review. Clin Cancer Res 2000; 6: 1205–1218.

    PubMed  CAS  Google Scholar 

  99. Kumar GN, Walle UK, Bhalla KN, Walle T. Binding of taxol to human plasma, albumin, and alpha 1-acid glycoprotein. Res Commun Chem Pathol Pharmacol 1993; 80: 337–344.

    PubMed  CAS  Google Scholar 

  100. Sparreboom A, Van Zuylen L, Brouwer E, et al. Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications. Cancer Res 1999; 59: 1454–1457.

    PubMed  CAS  Google Scholar 

  101. Burke TG, Zoorob G, Slatter JG, Schaaf LF. In vitro protein binding of CPT-11 metabolites SN-38, SN-38 glucuronide (SN-38G), and APC and possible displacement by commonly used co-medications. Proc Am Soc Clin Oncol 1998; 17: 195a (Abstr).

    Google Scholar 

  102. Ma M, Zamboni WC, Radomski KM, et al. Pharmacokinetics of irinotecan and its metabolites SN-38 and APC in children with recurrent solid tumors after protracted low-dose irinotecan. Clin Cancer Res 2000; 6: 813–819.

    PubMed  CAS  Google Scholar 

  103. Spila H, Nanto V, Kangas L, Anttila M, Halme T. Binding of toremifene to human serum proteins. Pharmacol Toxicol 1988; 63: 62–64.

    Article  Google Scholar 

  104. Shah IG, Parsons DL. Human albumin binding of tamoxifen in the presence of a perfluorochemical erythrocyte substitute. J Pharmaceut Pharmacol 1991; 43: 790–793.

    Article  CAS  Google Scholar 

  105. Petros WP, Rodman JH, Relling MV, et al. Variability in teniposide plasma protein binding is correlated with serum albumin concentrations. Pharmacotherapy 1992; 12: 273–277.

    PubMed  CAS  Google Scholar 

  106. Hagen B, Nilsen OG. The binding of thio-TEPA in human serum and to isolated serum protein fractions. Cancer Chemother Pharmacol 1987; 20: 319–323.

    Article  PubMed  CAS  Google Scholar 

  107. Burke TG, Mi Z. The structural basis of camptothecin interactions with human serum albumin: impact on drug stability. J Med Chem 1994; 37: 40–46.

    Article  PubMed  CAS  Google Scholar 

  108. Wall JG, Burris HA 3d, Von Hoff DD, et al. A phase I clinical and pharmacokinetic study of the topoisomerase I inhibitor topotecan (SKandF 104864) given as an intravenous bolus every 21 days. Anticancer Drugs 1992; 3: 337–345.

    Google Scholar 

  109. Fanucchi MP, Walsh TD, Fleisher M, et al. Phase I and clinical pharmacology study of trimetrexate administered weekly for three weeks. Cancer Res 1987; 47: 3303–3308.

    PubMed  CAS  Google Scholar 

  110. Fuse E, Tanii H, Kurata N, et al. Unpredicted clinical pharmacology of UCN-01 caused by specific binding to human ai-acid glycoprotein. Cancer Res 1998; 58: 3248–3253.

    PubMed  CAS  Google Scholar 

  111. Fuse E, Tanii H, Takai K, et al. Altered pharmacokinetics of a novel anticancer drug, UCN-01, caused by specific high affinity binding to ai-acid glycoprotein in humans. Cancer Res 1999; 59: 1054–1060.

    PubMed  CAS  Google Scholar 

  112. Steele WH, Haughton DJ, Barber HE. Binding of vinblastine to recrystallized human alpha 1-acid glycoprotein. Cancer Chemother Pharmacol 1982; 10: 40–42.

    Article  PubMed  CAS  Google Scholar 

  113. Steele WH, King DJ, Barber HE, Hawksworth GM, Dawson AA, Petrie JC. The protein binding of vinblastine in the serum of normal subjects and patients with Hodgkin’s disease. Eur J Clin Pharmacol 1983; 24: 683–687.

    Article  PubMed  CAS  Google Scholar 

  114. Urien S, Bree F, Breillout F, Bastian G, Krikorian A, Tillement JP. Vinorelbine high-affinity binding to human platelets and lymphocytes: distribution in human blood. Cancer Chemother Pharmacol 1993; 32: 231–234.

    Article  PubMed  CAS  Google Scholar 

  115. Rolan PE. Plasma protein binding displacement interactions why are they still regarded as clinically important? Br J Clin Pharmacol 1994; 37: 125–128.

    Article  PubMed  CAS  Google Scholar 

  116. Sansom LN, Evans AM. What is the true clinical significance of plasma protein binding displacement interactions? Drugs Safety 1995; 12: 227–233.

    Article  CAS  Google Scholar 

  117. Schwinghammer TL, Fleming RA, Rosenfeld CS, et al. Disposition of total and unbound etoposide following high-dose therapy. Cancer Chemother Pharmacol 1993; 32: 273–276.

    Article  PubMed  CAS  Google Scholar 

  118. Stewart CF, Arbuck SG, Fleming RA, et al. Changes in the clearance of total and unbound etoposide in patients with liver dysfunction. J Clin Oncol 1990; 8: 1874–1879.

    PubMed  CAS  Google Scholar 

  119. Fleming RA, Evans WE, Arbuck SG, et al. Factors affecting in vitro protein binding of etoposide in humans. J Pharmaceut Sci 1992; 81: 259–263.

    Article  CAS  Google Scholar 

  120. Stewart CF, Fleming RA, Arbuck SG, et al. Prospective evaluation of a model for predicting etoposide plasma protein binding in cancer patients. Cancer Res 1990; 50: 6854–6857.

    PubMed  CAS  Google Scholar 

  121. Stewart CF, Arbuck SG, Fleming RA, et al. Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther 1991; 50: 385–390.

    Article  PubMed  CAS  Google Scholar 

  122. Joel SP, Shah R, Slevin ML. Etoposide dosage and pharmacodynamics. Cancer Chemother Pharmacol 1994; 34: 69–75.

    Article  Google Scholar 

  123. Evans WE, Rodman JH, Relling MV, et al. Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphoblastic leukemia. J Pharmacol Exp Ther 1992; 260: 71–79.

    PubMed  CAS  Google Scholar 

  124. DeConti RC, Toftness BR, Lange RC, Creasey WA. Clinical and pharmacological studies with cisdiamminedichloroplatinum (II). Cancer Res 1973; 333: 1310–1315.

    Google Scholar 

  125. Gullo JJ, Litterst CL, Maguire PJ, Sikic BI, Hoth DF, Woolley PV. Pharmacokinetics and protein binding of cis-dichlorodiammine platinum (II) administered as a one hour or as a twenty hour infusion. Cancer Chemother Pharmacol 1980; 5: 21–26.

    Article  PubMed  CAS  Google Scholar 

  126. PereraF, Fischman HK, Hemminki K, et al. Protein binding, sister chromatid exchange and expression of oncogene proteins in patients treated with cisplatinum (cisDDP)-based chemotherapy. Arch Toxicol 1990; 64: 401–406.

    Article  Google Scholar 

  127. Takada K, Kawamura T, Inai M, et al. Irreversible binding of cisplatin in rat serum. Pharmaceut Pharmacol Commun 1999; 5: 449–453.

    Article  CAS  Google Scholar 

  128. Canal P. Platinum compounds: pharmacokinetics and pharmacodynamics. In: Grochow LB, Ames MM (eds). A Clinician’s Guide to Chemotherapy Pharmacokinetics and Pharmacodynamics. Baltimore: Williams and Williams, 1998, pp. 345–374.

    Google Scholar 

  129. Rahman A, Treat J, Roh JK, et al. A phase I clinical trial and pharmacokinetic evaluation of liposome-encapsulated doxorubicin. J Clin Oncol 1990; 8: 1093–1100.

    PubMed  CAS  Google Scholar 

  130. Cowens JW, Creaven PJ, Greco WR, et al. Initial clinical (phase I) trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res 1993; 53: 2796–2802.

    PubMed  CAS  Google Scholar 

  131. Gelmon KA, Tolcher A, Diab AR, et al. Phase I study of liposomal vincristine. J Clin Oncol 1999; 17: 697–705.

    PubMed  CAS  Google Scholar 

  132. Druckmann S, Gabizon A, Barenholtz Y. Separation of liposome-associated doxorubicin from nonliposome-associated doxorubicin in human plasma: implications for pharmacokinetic studies. Biochim Biophys Acta 1989; 980: 381–384.

    Article  PubMed  CAS  Google Scholar 

  133. Gabizon A, Catane R, Uziely B, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994; 54: 987–992.

    PubMed  CAS  Google Scholar 

  134. Thies RL, Cowens DW, Cullis PR, Bally MB, Mayer LD. Method for rapid separation of liposome-associated doxorubicin from free doxorubicin in plasma. Analyt Biochem 1990; 188: 65–71.

    Article  PubMed  CAS  Google Scholar 

  135. Mayer LD, St.-Onge G. Determination of free and liposome-associated doxorubicin and vincristine levels in plasma under equilibrium conditions employing ultrafiltration techniques. Analyt Biochem 1995; 232: 149–157.

    Article  PubMed  CAS  Google Scholar 

  136. Srigritsanapol AA, Chan KK. A rapid method for the separation and analysis of leaked and liposomal entrapped phosphoramide mustard in plasma J Pharmaceut Biomed Anal 1994; 12: 961–968.

    CAS  Google Scholar 

  137. Dipali SR, Kulkarni SB, Betageri GV. Comparative study of separation of non-encapsulated drug from unilamellar liposomes by various methods. J Pharmaceut Pharmacol 1996; 48: 1112–1115.

    Article  CAS  Google Scholar 

  138. Van Zuylen L, Karlsson MO, Verweij J, et al. Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles. Cancer Chemother Pharmacol 2001; 47: 309–318.

    Article  PubMed  CAS  Google Scholar 

  139. Van Zuylen L, Gianni L, Verweij J, et al. Interrelationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients. Anticancer Drugs 2000; 11: 331–337.

    Article  PubMed  Google Scholar 

  140. Brouwer E, Verweij J, De Bruijn P, et al. Measurement of fraction unbound paclitaxel in human plasma. Drug Metab Dispos 2000; 28: 1141–1145.

    PubMed  CAS  Google Scholar 

  141. Henningsson A, Karlsson MO, Vigano L, et al. Mechanism based pharmacokinetic model for paclitaxel. J Clin Oncol 2001; 19: 4065–4073.

    PubMed  CAS  Google Scholar 

  142. Kehrer DFS, Soepenberg O, Loos WJ, Verweij J, Sparreboom A. Modulation of camptothecin analogues in the treatment of cancer: a review. Anticancer Drugs 2001; 12: 89–106.

    Article  PubMed  CAS  Google Scholar 

  143. Mi Z, Burke TG. Differential interactions of camptothecin lactone and carboxylate forms with human blood components. Biochemistry 1994; 33:10, 325–10, 326.

    Google Scholar 

  144. Mi Z, Malak H, Burke TG. Reduced albumin binding promotes the stability and activity of topotecan in human blood. Biochemistry 1995; 34:13, 722–13, 728.

    Google Scholar 

  145. Mi Z, Burke TG. Marked interspecies variations concerning the interactions of camptothecin with serum albumins: a frequency-domain fluorescence spectroscopic study. Biochemistry 1994; 33: 12, 540–12, 545.

    Google Scholar 

  146. Loos WJ, Verweij J, Gelderblom AJ, et al. Role of erythrocytes and serum proteins in the kinetic profiles of total 9-amino-20(S)-camptothecin in humans. Anticancer Drugs 1999; 10: 705–710.

    Article  PubMed  CAS  Google Scholar 

  147. De longe MJA, Verweij J, Loos WJ, Dallaire BK, Sparreboom A. Clinical pharmacokinetics of oral 9-aminocamptothecin in plasma and saliva. Clin Pharmacol Ther 1999; 65: 491–499.

    Article  Google Scholar 

  148. Loos WJ, De Bruijn P, Verweij J, Sparreboom A. Determination of camptothecin analogues in biological matrices by high-performance liquid chromatography. Anticancer Drugs 2000; 11: 315–324.

    Article  PubMed  CAS  Google Scholar 

  149. Hervé F, Urien S, Albengres E, Duché JC, Tillement JP. Drug binding in plasma. A summary of recent trends in the study of drug and hormone binding. Clin Pharmacokinet 1994; 26: 44–58.

    Article  PubMed  Google Scholar 

  150. Roberts SA. High-throughput screening approaches for investigating drug metabolism and pharmacokinetics. Xenobiotica 2001; 31: 557–589.

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. Alex Sparreboom PhD
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  2. Walter J. Loos PhD
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Editors and Affiliations

  1. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    William D. Figg PharmD

  2. Washington University School of Medicine, St. Louis, MO, USA

    Howard L. McLeod PharmD

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Sparreboom, A., Loos, W.J. (2004). Protein Binding of Anticancer Drugs. In: Figg, W.D., McLeod, H.L. (eds) Handbook of Anticancer Pharmacokinetics and Pharmacodynamics. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-734-5_12

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  • DOI: https://doi.org/10.1007/978-1-59259-734-5_12

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