Summary
The distribution of3H-pethidine in whole blood was compared in old (63–86 years;n=11) and young (19–25 years,n=12) subjects using equilibrium dialysis. The plasma protein binding was 52.7±3.3% (mean ± SD) in the old subjects and 51.8±3.1% in the young; the difference was not statistically significant. Studies on isolated plasma protein fractions showed that the main pethidine-binding protein wasα 1-acid glycoprotein. Accordingly, the degree of pethidine binding is likely to be affected by inflammatory disease rather than by age. The distribution of pethidine to blood cells showed no age-related difference; the ratio between whole blood and plasma concentrations was 0.99 in old and 0.98 in young subjects. In whole blood from old and young subjects, 43% and 41% of pethidine was present in erythrocytes, 27% and 26% in plasma water whereas 30% and 29% was bound to plasma proteins. The mean ratio between pethidine in cells and plasma water (2.01) indicates binding of the drug in or on the blood cells. These in vitro results do not support the previous theory that a decrease in intracellular pethidine distribution in old age was the reason for the reported higher plasma levels. A slower elimination rate remains the most likely explanation for the increased plasma concentration of pethidine in old patients.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abshagen U, Kewitz H, Rietbrock N (1971) Distribution of digoxin, digitoxin and ouabain between plasma and erythrocytes in various species. Naunyn-Schmiedebergs Arch Pharmakol 270: 105–116
Bayne WF, Chu L-C, Theeuwes F (1979) Acetazolamide binding to two carbonic anhydrase isoenzymes in human erythrocytes. J Pharm Sci 68: 912–913
Beermann B, Hellström K, Lindström B, Rosén A (1975) Binding-site interaction of chlorthalidone and acetazolamide, two drugs transported by red blood cells. Clin Pharmacol Ther 17: 424–432
Bickel MH (1975) Binding of chlorpromazine and imipramine to red cells, albumin, lipoproteins and other blood components. J Pharm Pharmacol 27: 733–738
Boréus LO, Sköldefors E, Ehrnebo M (1982) Appearance of pethidine and norpethidine in cerebrospinal fluid of man following intramuscular injection of pethidine. (Submitted for publication)
Borgå O, Piafsky KM, Nilsen OG (1977) Plasma protein binding of basic drugs. I. Selective displacement fromα 1-acid glycoprotein by tris (2-butoxyethyl) phosphate. Clin Pharmacol Ther 22: 539–544
Borondy P, Dill WA, Chang T, Buchanan RA, Glazko AJ (1973) Effect of protein binding on the distribution of 5,5-diphenylhydantoin between plasma and red cells. Ann NY Acad Sci 226: 82–87
Caranasos GJ, Stewart RB, Cluff LE (1974) Drug-induced illness leading to hospitalization. J Am Med Assoc 228: 713–717
Chan K, Kendall MJ, Mitchard M, Wells WDE, Vickers MD (1975) The effect of ageing on plasma pethidine concentration. Br J Clin Pharmacol 2: 297–302
Crooks J, O'Malley K, Stevenson IH (1976) Pharmacokinetics in the elderly. Clin Pharmacokinet 1: 280–296
Denko CW, Gabriel P (1981) Age and sex related levels of albumin, ceruloplasmin,α 1-antitriypsin,α 1-acid glycoprotein, and transferrin. Ann Clin Lab Sci 11: 63–68
Ehrnebo M, Agurell S, Jalling B, Boréus LO (1971) Age differences in drug binding by plasma proteins: Studies on human foetuses, neonates and adults. Eur J Clin Pharmacol 3: 189–193
Ehrnebo M, Agurell S, Boréus LO, Gordon E, Lönroth U (1974) Pentazocine binding to blood cells and plasma proteins. Clin Pharmacol Ther 16: 424–429
Ehrnebo M, Odar-Cederlöf I (1975) Binding of amobarbital, pentobarbital and diphenylhydantoin to blood cells and plasma proteins in healthy volunteers and uraemic patients. Eur J Clin Pharmacol 8: 445–453
Elofsson R, Nilsson SO, Ågren A (1970) Complex formation between macromolecules and drugs. IV. Binding of sulfa drugs to human serum albumin at varying pH values. Acta Pharm Suec 7: 473–482
Fremstad D, Bergerud K, Haffner JFW, Lunde PKM (1976) Increased plasma binding of quinidine after surgery: A preliminary report. Eur J Clin Pharmacol 10: 441–444
Hayes MJ, Langman MJS, Short AH (1975) Changes in drug metabolism with increasing age: 1. Warfarin binding and plasma proteins. Br J Clin Pharmacol 2: 69–72
Hayes MJ, Langman MJS, Short AH (1975) Changes in drug metabolism with increasing age: 2. Phenytoin clearance and protein binding. Br J Clin Pharmacol 2: 73–79
Holmberg L, Odar-Cederlöf I, Boréus LO, Heyner L, Ehrnebo M (1982) Disposition of pethidine and norpethidine in old patients compared to young. Eur J Clin Pharmacol 22: 175–179
Hurwitz N (1969) Predisposing factors in adverse reactions to drugs. Br Med J 1: 536–539
Kurata D, Wilkinson GR (1974) Erythrocyte uptake and plasma binding of diphenylhydantoin. Clin Pharmacol Ther 6: 355–362
Kwant WO, Seeman P (1969) The membrane concentration of a local anesthetic (chlorpromazine). Biochim Biophys Acta 183: 530–543
Lunde PKM, Rane A, Yaffe SJ, Lund L, Sjöqvist F (1970) Plasma protein binding of diphenylhydantoin in man. Clin Pharmacol Ther 11: 846–855
Mather LE, Tucker GT, Pflug AE, Lindop MJ, Wilkerson C (1975) Meperidine kinetics in man: intravenous injection in surgical patients and volunteers. Clin Pharmacol Ther 17: 21–30
McArthur JN, Dawkins PD, Smith MJH (1971) The binding of indomethacin, salicylate and phenobarbitone to human whole blood in vitro. J Pharm Pharmacol 23: 32–36
Mitchard M (1979) Drug distribution in the elderly. In: Crooks J, Stevenson IH (eds) Drugs and the elderly. Perspectives in geriatric clinical pharmacology. MacMillan, London, pp 65–76
Nilsen OG, Jacobsen S (1975) The binding of quinidine to protein fractions of normal human sera. Biochem Pharmacol 24: 995–998
Piafsky KM, Borgå O (1977) Plasma protein binding of basic drugs. II. Importance ofα 1-acid glycoprotein for interindividual variation. Clin Pharmacol Ther 22: 545–549
Piafsky KM, Borgå O, Odar-Cederlöf I, Johansson C, Sjöqvist F (1978) Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasmaα 1-acid glycoprotein. N Engl J Med 299: 1435–1439
Richey DP, Bender AD (1977) Pharmacokinetic consequences of ageing. Annu Rev Pharmacol Toxicol 17: 49–65
Schanker LS, Nafpliotis PA, Johnson JM (1961) Passage of organic bases into human red cells. J Pharmacol Exp Ther 133: 325–331
Subbarao K, Rucinski B, Rausch MA, Schmid K, Niewiarowski S (1977) Binding of dipyridamole to human platelets and toα 1-acid glycoprotein and its significance for the inhibition of adenosine uptake. J Clin Invest 60: 936–943
Wallace S, Whiting B, Runcie J (1976) Factors affecting drug binding in plasma of elderly patients. Br J Clin Pharmacol 3: 327–330
Wallace SM, Riegelman S (1977) Uptake of azetazolamide by human erythrocytes in vitro. J Pharm Sci 66: 729–731
Wilkinson GR, Schenker S (1976) Pharmacokinetics of meperidine in man: Reply (Correspondence). Clin Pharmacol Ther 19: 486–488
Wind M, Berliner A, Stern A (1973) The binding of phenothiazines to oxyhemoglobin A and S. Res Commun Chem Pathol Pharmacol 5: 759–766
Woodford-Williams E, Alvarez A, Webster D, Landless B, Dixon MP (1964) Serum protein patterns in “normal” and pathological ageing. Gerontologia 10: 86–99
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Holmberg, L., Odar-Cederlöf, I., Nilsson, J.L.G. et al. Pethidine binding to blood cells and plasma proteins in old and young subjects. Eur J Clin Pharmacol 23, 457–461 (1982). https://doi.org/10.1007/BF00605998
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00605998