Advertisement

European Journal of Clinical Pharmacology

, Volume 24, Issue 6, pp 825–831 | Cite as

The binding of ketamine to plasma proteins: Emphasis on human plasma

  • P. G. Dayton
  • R. L. Stiller
  • D. R. Cook
  • J. M. Perel
Originals

Summary

We report for the first time that ketamine (K) is bound as much as 47% to human plasma. It was shown that binding of K to plasma and albumin is dependent on pH; binding is decreased at pH lower than 7.4 and increased at higher pH. This is in concordance with the pKa of K being 7.5; the partition coefficient between an organic phase and buffer was found to be sensitive to small pH changes. Binding of K is also influenced by albumin concentration and the affinity of K for human α1-acid glycoprotein (AAG) is much higher than for human albumin (HSA). The major metabolite nor-K does not appreciably displace K from binding sites on HSA. These findings may explain in part the variability of binding of K observed with different human samples. Human cord plasma exhibits a lower binding of K than adult plasma. This is probably the result of much lower AAG concentration in cord compared to adult plasma; cord and adult plasma albumin levels are known to be only slightly different. Since K has 2 optically active isomers, one of which is more potent than the other, experiments on the binding of racemic and the 2 isomers of K were performed; no differences in binding to AAG were found. We were, however, able to show that tris (butoxyethyl) phosphate (TBEP) can abolish binding of K to AAG. Thus the presence of TBEP would interfere in determining plasma levels and distribution of K. An example would be in the measurement of the partition of K between human red cells and plasma. We determined this ratio in human blood in the absence of TBEP and found it to be similar to that reported for dog red blood cells and plasma.

Key words

ketamine binding to plasma proteins alpha1-acid glycoprotein albumin pH change 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Adams JD Jr, Baillie TAS, Castagnoli N Jr (1981) Studies on the biotransformation of ketamine. Biomed Mass Spectrom 8: 527–538Google Scholar
  2. 2.
    Baggot JD, Blake JW (1976) Disposition kinetics of ketamine in the domestic cat. Arch Int Pharmacodyn 220: 115–124Google Scholar
  3. 3.
    Beckett AH, Chidomere EC (1977) The distribution, metabolism and excretion of mexiletine in man. Postgrad Med J [Suppl 1] 3: 60–66Google Scholar
  4. 4.
    Blackburn CE, Ober TE (1968) Tritium labelling of 2-(o-chlorophenyl)ethylaminecyclohexanone (ketamine, CI-581) by acid catalyzed exchange: An example of intramolecular competition for tritium between substituted aromatic and cyclohexanone rings. J Labelled Comp 3: 38–45Google Scholar
  5. 5.
    Borga G, Piafsky KM, Nilsen OG (1977) Plasma protein binding of basic drugs I. Selective displacement from alpha-1 acid glycoprotein by tris-butoxyethyl phosphate. Clin Pharmacol Ther 22: 539–544Google Scholar
  6. 6.
    Brem RF, Giardina EGV, Bigger JT (1982) Time course of alpha-1acid glycoprotein and its relationship to imipramine plasma protein binding. Clin Pharmacol Ther 31: 206Google Scholar
  7. 7.
    Brodie BB, Mark LC, Papper EM, Leif PA, Bernstein E, Rovenstine EA (1950) The fate of thiopental in man and a method for its estimation in biological material. J Pharmacol Exp Ther 98: 85–96Google Scholar
  8. 8.
    Castro MI, Rose J, Green W, Lehner N, Peterson D, Taub D (1981) Ketamine. HCl as a suitable anesthetic for endocrine, metabolic studies inMacaca fasicularis monkeys. Proc Soc Exp Biol Med 168: 389–394Google Scholar
  9. 9.
    Chang T, Glazko AJ (1974) Biotransformation and disposition of ketamine. Int Anesthesiol Clin 12: 157–177Google Scholar
  10. 10.
    Clements JA, Nimmo WS (1981) Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 53: 27–30Google Scholar
  11. 11.
    Cohen ML, Trevor A (1974) On the cerebral accumulation of ketamine and the relationship between metabolism of the drug and its pharmacological effect. J Pharmacol Exp Ther 189: 352–358Google Scholar
  12. 12.
    Edwards DJ, Lalka D, Cerra G, Slaughter RL (1982) Alpha-1 acid glycoprotein concentration and protein binding in trauma. Clin Pharmacol Ther 31: 62–67Google Scholar
  13. 13.
    Giles HG, Corrigall WA, Sellers EM (1982) Plasma protein binding of phencyclidine. Clin Pharmacol Ther 31: 77–82Google Scholar
  14. 14.
    Grant IS, Nimmo WS, Clements JA (1981) Pharmacokinetics and analgesic effects of i.v. and oral ketamine. Br J Anaesth 53: 805–810Google Scholar
  15. 15.
    Grossman SH, Davis D, Kitchell BB, Shand D, Routledge PA (1982) Diazepam and lidocaine plasma protein binding in renal disease. Clin Pharmacol Ther 31: 350–357Google Scholar
  16. 16.
    Idvall L, Ahlgren J, Aaronsen KF, Stenberg P (1979) Ketamine infusions: Pharmacokinetics and clinical effect. Br J Anaesth 51: 1167–1173Google Scholar
  17. 17.
    Jackson APF, Dhalpale PR, Callaghan M, Alseri S (1978) Hemodynamic Studies during induction of anesthesia for open heart surgery using diazepam and ketamine. Br J Anesth 50: 375–379Google Scholar
  18. 18.
    Lima JJ, Salzer LB (1981) Contamination of albumin by alpha-1 acid glycoprotein. Biochem Pharmacol 30: 2633–2636Google Scholar
  19. 19.
    Little B, Chant T, Chucot L, Dill WA, Enrite LL, Glazko AJ, Jasani M, Kretchmer H, Sweet AY (1972) Study of ketamine as an obstetric anesthetic agent. Am J Obstet Gynecol 113: 247–260Google Scholar
  20. 20.
    Lo JM, Cummings SF (1976) Interaction between sedative premedicants and ketamine in man and isolated perfused rat livers. Anesthesiology 43: 307–312Google Scholar
  21. 21.
    Kaka JS, Hayton WL (1980) Pharmacokinetics of ketamine and two metabolites in the dog. J Pharmacokinet Biopharmaceut 8: 193–202Google Scholar
  22. 22.
    Kaka JS, Hayton WL (1979) Pharmacokinetics of ketamine in the horse. Am J Vet Res 40: 978–981Google Scholar
  23. 23.
    Kornguth ML, Hutchins LG, Eichelman BS (1981) Binding of psychotropic drugs to isolated alpha-1 acid glycoprotein. Biochem Pharmacol 30: 2435–2441Google Scholar
  24. 24.
    Nation RL (1981) Meperidine binding in maternal and fetal plasma. Clin Pharmacol Ther 29: 472–479Google Scholar
  25. 25.
    Perel JM, Stiller RL, Lin F, Narayanan S (1983) Commentary. Re-evaluation of currently produced vacutainer blood collection tubes for selected drug analysis. Ther Drug Mon (submitted for publication)Google Scholar
  26. 26.
    Petersen MC, Vine J, Ashley JJ, Nation RL (1981) Leaching of 2-(2-hydroxyethylmercapto) benzothiazole into contents of disposable syringes. J Pharm Sci 70: 1139–1143Google Scholar
  27. 27.
    Piafsky KM (1980) Disease-induced changes in the plasma binding of basic drugs. Clin Pharmacokinet 5: 246–262Google Scholar
  28. 28.
    Piafsky KM, Borga O, Odar-Cederlog I, Johansson C, Sjöqvist F (1978) Increased plasma protein binding of propanolol and chlorpromazine mediated by disease-induced elevations of plasma acid glycoprotein. N Engl J Med 299: 1435–1439Google Scholar
  29. 29.
    Pike E, Skuterud B, Kierugg P, Fredstad D, Abdel Sayed SM, Lunde PKM (1981) Binding and displacement of basic, acidic and neutral Drugs in normal and orosomucoid-deficient plasma. Clin Pharmacokinet 6: 367–374Google Scholar
  30. 30.
    Pirkle WH, House DW, Finn JM (1980) Broad spectrum resolution optical isomers using chiral high performance liquid chromatography. J Chromatogr 192: 143Google Scholar
  31. 31.
    Pruitt AW, Dayton PG (1971) A comparison of the binding of drugs to adult and cord plasma. Eur J Clin Pharmacol 4: 59Google Scholar
  32. 32.
    Rall DP, Zubrod CG (1962) Mechanism of drug absorption and excretion. Passage of drugs in and out of the central nervous system. Annu Rev Pharmacol 2: 109–128Google Scholar
  33. 33.
    Schley J, Seigert M, Muller-Oerlinghausen B (1980) Binding of perazine to alpha-1 acid glycoprotein. Eur J Clin Pharmacol 18: 501–504Google Scholar
  34. 34.
    Schuppel R, Zange J, Durr W, Petruch F (1970) Untersuchungen zur Wirkungsinterferenz von Ketamine (Ketanest) und Äthanol. Naunyn Schmiedeberg's Arch Pharmacol 266: 447–448Google Scholar
  35. 35.
    Wadell WJ, Butler TC (1957) The distribution and excretion of phenobarbital. J Clin Invest 36: 1217–1226Google Scholar
  36. 36.
    White PF, Han J, Way SL, Trevor AJ (1980) Pharmacology of ketamine isomers in surgical patients. Anesthesiology 52: 231–239Google Scholar
  37. 37.
    White PF, Way WL, Trevor A (1982) Ketamine. Pharmacology and therapeutic use. Anesthesiology 56: 119–136Google Scholar
  38. 38.
    Wieber J, Gugler R, Hengstmann JH, Dengler HJ (1975) Pharmacokinetics of ketamine in man. Anaesthesist 24: 260–263Google Scholar
  39. 39.
    Wood J, Wood AJJ (1981) Changes in plasma drug binding and alpha-1 acid glycoprotein in mother and newborn infant. Clin Pharmacol Ther 29: 522–526Google Scholar
  40. 40.
    Zsigmond EK, Domino EF (1980) Ketamine, clinical pharmacology, pharmacokinetics and current clinical uses. Anesthesiol Rev 7: 13–22Google Scholar

Copyright information

© Springer-Verlag 1983

Authors and Affiliations

  • P. G. Dayton
    • 1
  • R. L. Stiller
    • 1
  • D. R. Cook
    • 2
  • J. M. Perel
    • 1
    • 3
  1. 1.Department of Psychiatry, Western Psychiatric Institute and ClinicUniversity of PittsburghPittsburghUSA
  2. 2.Department of Anesthesiology, Children's HospitalUniversity of PittsburghPittsburghUSA
  3. 3.Department of PharmacologyUniversity of PittsburghPittsburghUSA

Personalised recommendations