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Effect of Binding to Plasma Proteins on the Distribution, Activity and Elimination of Drugs

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Concepts in Biochemical Pharmacology

Abstract

The binding of a drug to plasma proteins is of importance in so far as it modifies the pharmacological activity of that drug. Protein-binding may affect drug activity in one of two ways: either by changing the effective concentration of the drug at its site of action or by changing the rate at which the drug is eliminated, thus affecting the length of time for which effective concentrations are maintained. In this chapter Section A deals with the effects of protein-binding on drug distribution and hence on activity; Section B discusses the ways in which protein- binding can affect drug elimination and Section C attempts a quantitative analysis of the ways in which these various factors interact in drug kinetics.

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References

  • Aladjemoff, L., Dikstein, S., Shafrir, E.: The binding of d-tubocurarine chloride to plasma proteins. J. Pharmacol, exp. Ther. 123, 43–47 (1958).

    CAS  Google Scholar 

  • Anton, A. H.: The relation between the binding of sulfonamides to albumin and their antibacterial efficacy. J. Pharmacol, exp. Ther. 129, 282–290 (1960).

    CAS  Google Scholar 

  • Anton, A. H., A drug-induced change in the distribution and renal excretion of sulfonamides. J. Pharmacol. exp. Ther. 134, 291–303 (1961).

    PubMed  CAS  Google Scholar 

  • Anton, A. H., Boyle, J. J.: Alteration of the acetylation of sulfonamides by protein binding, sulfinpyrazone and suramin. Canad. J. Physiol. Pharmacol. 42, 809–817 (1964).

    Article  CAS  Google Scholar 

  • Bell, G.H., Davidson, J.N., Scarborough, H.: Textbook of Physiology and Biochemistry, 7th ed. p. 749, Edinburgh: Livingstone 1968

    Google Scholar 

  • Bennhold, H.: Transport function of the serum proteins. In: Transport function of plasma proteins, Desgrez, P., and P.M. De Traverse (Eds.). Amsterdam: Elsevier 1966.

    Google Scholar 

  • Bertazzoli, C., Chieli, T., Ciceri, C.: The metabolism of some sulphonamides in regard to the duration of their action in experimental animals. Biochem. Pharmacol. 11, 733–741 (1962).

    Article  CAS  Google Scholar 

  • Blecher, M.: Serum protein-steroid hormone interactions. Effects of glucocorticoids on glucose metabolism in rat adipose isolated cells, and the influence of human plasma corticosteroid binding protein. Endocrinology 79, 541–546 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Bond, J.M., Lightbown, J.W., Barber, M., Waterworth, P.M.: A comparison of four phenoxypenicillins. Brit. med. J. 2, 956–961 (1963).

    Article  PubMed  CAS  Google Scholar 

  • Bradbury, M.W., Davson, H.: The blood-brain barrier. In: Absorption and distribution of drugs, Binns, T.B. (Ed.). Edinburgh: Livingstone 1964.

    Google Scholar 

  • Bradley, S.E., Ingelfinger, P. J., Bradley, G.P.: Hepatic circulation in cirrhosis of the liver. Circulation 5, 419–429 (1952).

    PubMed  CAS  Google Scholar 

  • Bratjer, R.W., Pessotti, R.L.: The removal of bromsulphthalein from blood plasma by the liver of the rat. J. Pharmacol, exp. Ther. 97, 358–370 (1959).

    Google Scholar 

  • Brodie, B.B., Hogben, C.A.M.: Some physicochemical factors in drug action. J. Pharm. Pharmacol. 9, 345–380 (1957).

    Article  PubMed  CAS  Google Scholar 

  • Brodie, B.B., Hogben, C.A.M., Kurz, H., Schanker, L. S.: The importance of dissociation constant and lipid-solubility in influencing the passage of drugs into the cerebrospinal fluid. J. Pharmacol, exp. Ther. 130, 20–25 (1960).

    CAS  Google Scholar 

  • Brown, D.M.: Tissue distribution of penicillins. Postgrad, med. J. Suppl. 40, 31–36 (1964).

    Google Scholar 

  • Burns, J. J., Rose, R.K., Chenkin, T., Goldman, A., Schulert, A., Brodie, B.B.: The physiological disposition of phenylbutazone (Butazolidin) in man and a method for its estimation in biological material. J. Pharmacol, exp. Ther. 109, 346–357 (1953).

    CAS  Google Scholar 

  • Butler, T. C.: Termination of drug action by elimination of unchanged drug. Fed. Proc. 17, 1158–1162 (1958).

    PubMed  CAS  Google Scholar 

  • Combes, B., Wheeler, H.O., Childs, A.W., Bradley, S.E.: The mechanisms of bromsulfalein removal from the blood. Trans. Ass. Amer. Phycns. 69, 276–284 (1956).

    CAS  Google Scholar 

  • Conn, H.L., Luchi, R.J.: Some quantitative aspects of the binding of quinidine and related quinoline compounds by human serum albumin. J. clin. Invest. 40, 509–516 (1961).

    Article  PubMed  CAS  Google Scholar 

  • Craig, L.C., King, T.P., Stracher, A.: Dialysis studies II Some experiments dealing with the problem of selectivity. J. Amer. chem. Soc. 79, 3729–3737 (1957).

    Article  CAS  Google Scholar 

  • Dayton, P.G., Brand, L., Taller, D., Mark, L.C.:: Passage of thiopental and barbital into ocular and cerebrospinal fluids of dogs. Proc. Soc. exp. Biol. (N.Y.) 107, 180–183 (1961).

    CAS  Google Scholar 

  • Dayton, P.G., Brand, L., Taller, D., Perel, J.M., Landrau, M.A., Brand, L., Mark, L.C.: The relationship between binding of thiopental to plasma and its distribution into adipose tissue in man, as measured by a spectrophotofluorometric method. Biochem. Pharmacol. 16, 2321–2326 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Eagle, H., Newman, E.: The renal clearance of penicillins F, G, K and X in rabbits and man. J. clin. Invest. 26, 903–918 (1947).

    Article  CAS  Google Scholar 

  • Farah, A.: On the combination of some cardio-active glycosides with serum proteins. J. Pharmacol, exp. Ther. 83, 143–157 (1945).

    CAS  Google Scholar 

  • Fawaz, G., Farah, A.: A study of the digitoxin binding power of serum and other soluble tissue-proteins of the rabbit. J. Pharmacol, exp. Ther. 80, 193–198 (1944).

    CAS  Google Scholar 

  • Fox, S.L.: Potentiation of anticoagulants caused by pyrazole compounds. J. Amer. med. Ass. 188, 320–321 (1964).

    CAS  Google Scholar 

  • Froese, A., Sehon, A.H., Eigen, M.: Kinetic studies of protein-dye and antibody-hapten interactions with the temperature-jump method. Canad. J. Chem. 40, 1786–1797 (1962).

    Article  CAS  Google Scholar 

  • Genazzani, E., Pagnini, G., Di Carlo, K.: Influence of different drugs on the sulfonamides serum binding and on sulfonamide aqueous humor levels. Proc. Ill int. Pharmacol. Meeting–1966 7, 181–187 (1968).

    Google Scholar 

  • Goldstein, A.: The interactions of drugs and plasma proteins. Pharmacol. Rev. 1, 102–165 (1949).

    Google Scholar 

  • Goldstein, A., Aronow, L., Kalman, S.M.: Principles of drug action, p. 184. New York: Harper and Bow 1968.

    Google Scholar 

  • Gourevitch, A., Hunt, G.A., Lein, H.: Structure-activity relationships in a series of synthetic penicillins. Antibiot. and Chemother. 10, 121–128 (1960).

    CAS  Google Scholar 

  • Holder, L.B., Hayes, S.L.: Diffusion of sulphonamides in aqueous buffers and into red cells. Molec. Pharmacol. 1, 266–279 (1965).

    CAS  Google Scholar 

  • Iversen, L. L.: The uptake of noradrenaline by the isolated perfused rat heart. Brit. J. Pharmacol. 21, 523–537 (1963).

    PubMed  CAS  Google Scholar 

  • Keen, P. M.: The binding of three penicillins in the plasma of several mammalian species as studied by ultrafiltration at body temperature. Brit. J. Pharmacol. 25, 507–514 (1965).

    PubMed  CAS  Google Scholar 

  • Keen, P. M., The binding of penicillins to bovine serum albumin. Biochem. Pharmacol. 15, 447–463 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Knoefel, P.K.: Radiopaque diagnostic agents. Ann. Rev. Pharmacol. 5, 321–334 (1965).

    Article  CAS  Google Scholar 

  • Kruger-Thiemer, E.: Solution of pharmacological problems by computers. 6. Models for the effect of protein-binding on the clearance of drugs. Arzneimittel-Forsch. 16, 1431–1442 (1966).

    CAS  Google Scholar 

  • Kruger-Thiemer, E. Pharmacokinetics and dose-concentration relationships. Proc. III int. Pharmacol. Meeting–1966 7, 63–113 (1968).

    Google Scholar 

  • Kruger-Thiemer, E., Diller, W., Bunger, P.: Pharmacokinetic models regarding protein binding of drugs. Antimicrob. Agents. Chemother. 1965, 183–191 (1966).

    Google Scholar 

  • Künin, C. M.: Comparative serum-binding, distribution and excretion of tetracycline and a new analogue, methacycline. Proc. Soc. exp. Biol. (N.Y.) 110, 311–315 (1962).

    Google Scholar 

  • Künin, C. M., Enhancement of antimicrobial activity of penicillins and other antibiotics in human serum by competitive serum binding inhibitors. Proc. Soc. exp. Biol. (N.Y.) 117, 69–73 (1964).

    Google Scholar 

  • Künin, C. M., Effect of serum binding on the distribution of penicillins in the rabbit. J. Lab. clin. Med. 65, 406 - 415 (1965).

    PubMed  Google Scholar 

  • Künin, C. M., Therapeutic implications of serum protein binding of the new semi-synthetic penicillins. Antimicrob. Agents Chemother. 1965, 1025–1034 (1966).

    Google Scholar 

  • Künin, C. M., Dornbttsh, A.C., Finland, M.: Distribution and excretion of four tetracycline analogues in normal young men. J. clin. Invest. 38, 1950–1963 (1959).

    Article  PubMed  Google Scholar 

  • Kuntzman, R., Tsai, I., Burns, J. J.: Importance of tissue and plasma binding in determining the retention of norchlorcyclizine and norcyclizine in man dog and rat. J. Pharmacol, exp. Ther. 158, 332–339 (1967).

    CAS  Google Scholar 

  • Lasser, E.C., Farr, R.S., Fujimagari, T., Tripp, W.N.: The significance of protein binding of contrast media in roentgen diagnosis. Amer. J. Roentgenol. 87, 338–365 (1962).

    PubMed  CAS  Google Scholar 

  • Lithander, A., Lithander, B.: The passage of penicillin into the cerebrospinal fluid after parenteral administration in staphylococcic meningitis. Acta path, microbiol. scand. 56, 435–450 (1962).

    Article  CAS  Google Scholar 

  • Lukas, D.S., Martino, A.G.D.: Binding of digitoxin and some related cardenolides to human plasma proteins. J. clin. Invest. 48, 1041–1053 (1969).

    Article  PubMed  CAS  Google Scholar 

  • Lullman, H., Van Zwieten, P.A.: The kinetic behaviour of cardiac glycosides in vivo, measured by isotope techniques. J. Pharm. Pharmacol. 21, 1–8 (1969).

    Article  Google Scholar 

  • Madsen, S.T., Ovsthus, O., Boe, J.: Antibacterial activity of long-acting sulphonamides. Acta med. scand. 173, 707–717 (1963).

    Article  Google Scholar 

  • Mark, L.C., Perel, J.M., Brand, L., Dayton, P.G.: Studies with thiohexital, an anaesthetic barbiturate metabolised with unusual rapidity in man. Anesthesiology 29, 1159–1166 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Marshall, E.K.: The secretion of phenol red by the mammalian kidney. Amer. J. Physiol. 99, 77–86 (1931).

    CAS  Google Scholar 

  • Martin, B.K.: Potential effect of the plasma proteins on drug distribution. Nature (Lond.) 207, 274–276 (1965).

    Article  CAS  Google Scholar 

  • Mayer, S., Maickel, R.P., Brodie, B.B.: Kinetics of penetration of drugs and other foreign compounds into cerebrospinal fluid and brain. J. Pharmacol, exp. Ther. 127, 205–211 (1959).

    CAS  Google Scholar 

  • Mccune, R.: Delivery of antimicrobial drugs across inflammatory membrane in rabbits. J. clin. Invest. 39, 846–853 (I960).

    Google Scholar 

  • Mcqueen, E.G.: Comparison of tissue fluid and plasma concentrations of a protein-bound drug sulphormethoxine by in vivo dialysis in rats. Brit. J. Pharmacol. 33, 312–328 (1968).

    PubMed  CAS  Google Scholar 

  • Mcqueen, E.G., Displacement from protein-binding of sulphormethoxine by phenylbutazone using in vivo dialysis in rats. Brit. J. Pharmacol. 36, 29–34 (1969).

    CAS  Google Scholar 

  • Meyer, M.C., Guttman, D.E.: The binding of drugs by plasma proteins. J. pharm. Sci. 57, 895–917 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Newbould, B.B., Kilpatrick, R.: Long-acting sulphonamides and protein-binding. Lancet 1, 887–891 (1960).

    Article  PubMed  CAS  Google Scholar 

  • Odell, G.B.: The dissociation of bilirubin from albumin and its clinical implications. J. Pediat. 55, 268–279 (1959).

    Article  PubMed  CAS  Google Scholar 

  • O’Reilly, R.A.: Studies on the coumarin anticoagulant drugs: interaction of human plasma albumin and warfarin sodium. J. clin. Invest. 46, 829–837 (1967).

    Article  PubMed  Google Scholar 

  • Van Os, G.A.J., Ariens, E.J., Simonis, A.M.: Molecular Pharmacology, Vol. 1. New York: Academic Press 1964.

    Google Scholar 

  • Pappenheimer, J. R.: Passage of molecules through capillary walls. Physiol. Rev. 33, 387–423 (1953).

    PubMed  CAS  Google Scholar 

  • Pitts, R.F.: Physiology of the kidney and body fluids, p. 117. Chicago: Year Book Medical Publishers 1963.

    Google Scholar 

  • Portwich, F., Buttner, H., Engelhardt, K.: Nierenausscheidung und EiweiBbindung von Sulfonamides Klin. Wschr. 41, 447–451 (1963).

    Article  CAS  Google Scholar 

  • Priestly, B.G., O’Reilly, W.J.: Protein binding and the excretion of some azo dyes in rat bile. J. Pharm. Pharmacol. 18, 41–45 (1966).

    Article  PubMed  CAS  Google Scholar 

  • Quinn, E.L.: Protein binding of semisynthetic penicillins. Postgrad, med. J. 40, 23–30 (1964).

    Article  CAS  Google Scholar 

  • Quinn, E.L., Colville, J.M., Ballard, L., Jones, D., Debnam, F.: Ampicillin: antimicrobial activity and pharmacological behaviour with reference to certain Gram-positive cocci. Antimicrob. Agents Chemother 1962, 339–349 (1963).

    CAS  Google Scholar 

  • Rasmtjssen, F.: Mammary excretion of sulphonamides. Acta pharmacol. (Kbh.) 15, 139–148 (1958).

    Article  Google Scholar 

  • Rasmtjssen, F. Mammary excretion of benzylpenicillin, erythromycin and penethamate hydroiodide. Acta pharmacol. (Kbh.) 16, 194–200 (1959).

    Article  Google Scholar 

  • Rasmtjssen, F. Salivary excretion of sulphonamides and barbiturates by cows and goats. Acta pharmacol. (Kbh.) 21, 11–19 (1964).

    Article  Google Scholar 

  • Reynolds, R. C., Cluff, L. E.: Interaction of serum and sodium salicylate: changes during acute infection and its influence on pharmacological activity. Bull. Johns Hopk. Hosp. 107, 278–290 (1960).

    CAS  Google Scholar 

  • Roberts, C.E., Perry, D.M., Kuharic, H.A., Kirby, W.M.M.: Demethylchlortetracycline and tetracycline. Arch, intern. Med. 107, 204–211 (1961).

    CAS  Google Scholar 

  • Rolinson, G.N.: The significance of protein-binding of antibiotics in vitro and in vivo. In: Recent advances in medical microbiology. Waterson, A.P. (Ed.). p. 254. London: Churchill 1967.

    Google Scholar 

  • Rolinson, G.N., Sutherland, R.: The binding of antibiotics to serum proteins. Brit. J. Pharmacol. 25, 638–650 (1965).

    PubMed  CAS  Google Scholar 

  • Ruedy, J.: The concentrations of penicillins in the cerebrospinal fluid and brain of rabbits with experimental meningitis. Canad. J. Physiol. Pharmacol. 43, 763–772 (1965).

    Article  CAS  Google Scholar 

  • Schanker, L.S.: Passage of drugs across body membranes. Pharmacol. Rev. 14, 501–530 (1962).

    PubMed  CAS  Google Scholar 

  • Silverman, W.A., Andersen, D.H., Blanc, W.A., Crozier, D.N.: A difference in mortality rate and incidence of kernicterus among premature infants allotted to two prophylactic antibacterial regimens. Pediatrics 18, 614–625 (1956).

    PubMed  Google Scholar 

  • Sirota, J.H., Saltzman, A.: The renal clearance and plasma protein binding of aureomycin in man. J. Pharmacol, exp. Ther. 100, 210–218 (1950).

    CAS  Google Scholar 

  • Sparr, R.A., Pritchard, J.A.: Maternal and newborn distribution and excretion of sulfa- methoxypyridazine (Kynex). Obstet, and Gynec. 12, 131–134 (1958).

    CAS  Google Scholar 

  • Taylor, J.D., Richards, R.K., Davin, J.C., Asher, J.: Plasma binding of thiopental in the nephrectomized rabbit. J. Pharmacol, exp. Ther. 112, 40–48 (1954).

    CAS  Google Scholar 

  • Thorp, J.M.: The influence of plasma proteins on the action of drugs. In: Absorption and distribution of drugs. Binns, T.B. (Ed.). Edinburgh: Livingstone 1964.

    Google Scholar 

  • Ungar, J.: Penicillin in tissue exudates after injection. Lancet 1, 56–59 (1950).

    Article  PubMed  CAS  Google Scholar 

  • Verwey, W.F., Williams, H.R.: Relationships between the concentrations of various penicillins in plasma and peripheral lymph. Antimicrob. Agents Chemother. 1962, 476–483 (1963a).

    Google Scholar 

  • Verwey, W.F., Williams, H.R., Binding of various penicillins by plasma and peripheral lymph obtained from dogs. Antimicrob. Agents Chemother. 1962, 484–491 (1963b).

    Google Scholar 

  • Kalsow, C.: Penetration of chemotherapeutic agents into tissues. Antimicrob. Agents Chemother. 1965, 1016–1024 (1966).

    Google Scholar 

  • Waddell, W.J., Butler, T.C.: Calculation of intracellular pH from the distribution of 5,5-dimethyl-2,4-oxazolidinedione (DMO). Application to skeletal muscle of the dog. J. clin. Invest. 38, 720–729 (1959).

    Article  PubMed  CAS  Google Scholar 

  • Wagner, J.G.: Pharmacokinetics. Ann. Rev. Pharmacol. 8, 67–94 (1968).

    Article  PubMed  CAS  Google Scholar 

  • Verwey, W.F., Williams, H.R. Northam, J.I.: Estimation of volume of distribution and half-life of a compound after rapid intravenous injection. J. pharm. Sci. 56, 529–531 (1967).

    Article  Google Scholar 

  • Warren, G. H.: The prognostic significance of penicillin serum levels and protein binding in clinical medicine. A review of current studies. Chemotherapia (Basel) 10, 339–358 (1966).

    CAS  Google Scholar 

  • Warren, G. H. Gray, J.: Effect of sublethal concentrations of penicillins on the lysis of bacteria by lysozyme and trypsin. Proc. Soc. exp. Biol. (N. Y.) 120, 504–511 (1965).

    CAS  Google Scholar 

  • Weiner, I. M.: Mechanisms of drug absorption and excretion. The renal excretion of drugs and related compounds. Ann. Rev. Pharmacol. 7, 39–56 (1967).

    Article  PubMed  CAS  Google Scholar 

  • Wolfe, R.N., Mcguire, J.M.: The use of blood serum as test medium in the in vitro evaluation of antibiotics. Antimicrob. Agents Annual. 1960, 167–171 (1961).

    Google Scholar 

  • Wurzel, M., Bacon, R.C., Kalt, R.B., Zweifach, B.W.: Vasoactive properties of plasma protein fractions. Amer. J. Physiol. 206, 923–925 (1964).

    PubMed  CAS  Google Scholar 

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Keen, P. (1971). Effect of Binding to Plasma Proteins on the Distribution, Activity and Elimination of Drugs. In: Brodie, B.B., Gillette, J.R., Ackerman, H.S. (eds) Concepts in Biochemical Pharmacology. Handbuch der experimentellen Pharmakologie/Handbook of Experimental Pharmacology, vol 28 / 1. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-65052-9_10

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