Summary
The binding of pentobarbital, diphenylhydantoin and salicylic acid to cells in blood was found to be independent of total drug concentration within therapeutic levels. Salicylic acid displaced pentobarbital and diphenylhydantoin from plasma protein binding sites, but high levels of salicylic acid had no effect on the distribution of the other two drugs to washed blood cells. Thus, in whole blood the presence of salicylic acid decreased the fraction of pentobarbital or diphenylhydantoin bound to plasma protiens and increased the fraction of the drug in plasma water and in blood cells. Diphenylhydantoin was shown not to be bound irreversibly to blood cells and equilibration in between the inside and outside of the cells was found to be rapid (within 5 min), even at high concentrations. Binding to washed blood cells was the same at 37°C and 25°C, in contrast to plasma protein binding. It is pointed out that these effects may cause certain analytical errors, resulting in changes in plasma concentration if plasma is separated at a low temperature.
Similar content being viewed by others
References
Lunde, P. K. M., Rane, A., Yaffe, S. J., Lund, L., Sjöqvist, F.: Plasma protein binding of diphenylhydantoin in man. Interaction with other drugs and the effect of temperature and plasma dilution. Clin. Pharmacol. Ther.11, 846–855 (1970)
Kurata, D., Wilkinson, G. R.: Erythrocyte uptake and plasma binding of diphenylhydantoin. Clin. Pharmacol. Ther.16, 355–362 (1974)
Ehrnebo, M., Odar-Cederlöf, I.: The binding of amobarbital, pentobarbital and diphenylhydantoin to blood cells and plasma proteins in healthy volunteers and uremic patients. Europ. J. clin. Pharmacol.8, 445–453 (1975)
McArthur, J. N., Dawkins, P. O., Smith, M. J. H.: The binding of indomethacin, salicylate and phenobarbitone to human whole blood in vitro. J. Pharm. Pharmacol.23, 32–36 (1971)
Ehrnebo, M., Agurell, S., Boréus, L. O., Gordon, E., Lönroth, U.: Binding of pentazocine to blood cells and plasma proteins in man. Clin. Pharmacol. Ther.16, 424–429 (1974)
Spector, R., Korkin, D. T., Lorenzo, A. V.: A rapid method for the determination of salicylate binding by the use of ultra filters. J. Pharm. Pharmacol.24, 786–789 (1972)
Meyer, M., Guttman, D.: The binding of drugs by plasma proteins. J. pharm. Sci.57, 895–918 (1968)
Brånstad, J. O., Meresaar, U., Agren, A.: Complex formation between macromolecules and drugs. VII. The binding of some barbiturates to human serum albumin (HSA) at varying pH. Acta pharm. suec.9, 129–134 (1972)
Schanker, L. S., Johnson, J. M., Jeffrey, J. J.: Rapid passage of organic anions into human red cells. Amer. J. Physiol.207, 503–508 (1964)
Antonini, E., Wyman, J., Moretti, R., Rossi-Fanelli, A.: The interaction of bromthymolblue with hemoglobin and its effect on the oxygen equilibrium. Biochem. biophys. Acta (Amst.)71, 124–138 (1963)
Kiehs, K., Hansch, C., Moore, L.: The role of hydrophobic bonding in the binding of organic compounds by bovine hemoglobin. Biochemistry5, 2602–2605 (1968)
Wind, M., Berliner, A., Stern, A.: The binding of phenothiazines to oxyhemoglobin A and S. Res. Commun. Chem. Pathol. Pharmacol.5, 759–766 (1973)
Bucci, E.: Electrostatic interaction of hemoglobin and benzenepentacarboxylate. Biochemistry13, 814–820 (1974)
Nilsson, S. O., Agren, A., Brånstad, J. O., Meresaar, U.: Complex formation between macromolecules and drugs. IX. The competition between two sulfa drugs and phenobarbital, pentobarbital or phenoxymethyl penicillin for binding sites on human serum albumin. Acta pharm. suec.10, 455–468 (1973)
Pagnini, G., DiCarlo, R., DiCarlo, F., Genazzani, E.: Enhancement of pentobarbital narcosis by drugs competing on the serum protein binding. Biochem. Pharmacol.20, 3247–3254 (1971)
Ehrnebo, M.: Pharmacokinetics and distribution properties of pentobarbital in humans following oral and intravenous administration. J. pharm. Sci.63, 1114–1118 (1974)
Odar-Cederlöf, I., Borgå, O.: Kinetics of diphenylhydantoin in uremic patients: Consequences of decreased plasma protein binding. Europ. J. clin. Pharmacol.7, 31–38 (1974)
Gilette, J. R.: Overview of drug-protein binding. Ann. N. Y. Acad. Sci.226, 6–17 (1973)
Klocke, R. A., Andersson, K. K., Rotman, H. H., Forster, R. E.: Permeability of human erythrocytes to ammonia and weak acids. Amer. J. Physiol.222, 1004–1013 (1972)
Ehrnebo, M., Agurell, S., Jalling, B., Boréus, L. O.: Age differences in drug binding by plasma proteins: Studies on human foetuses, neonates and adults. Europ. J. clin. Pharmacol.3, 189–193 (1971)
Anton, A. H., Corey, W. T.: Interindividual differences in the protein binding of sulfonamides: The effect of disease and drugs. Acta pharmacol. (Kbh.)29 (Suppl. 3), 134–151 (1971)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Ehrnebo, M., Odar-Cederlöf, I. Distribution of pentobarbital and diphenylhydantoin between plasma and cells in blood: Effect of salicylic acid, temperature and total drug concentration. Eur J Clin Pharmacol 11, 37–42 (1977). https://doi.org/10.1007/BF00561786
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00561786