Clinical Pharmacokinetics

, Volume 17, Issue 5, pp 308–326 | Cite as

Pharmacokinetic Implications for the Clinical Use of Propofol

  • J. Kanto
  • E. Gepts
Review Article Drug Disposition

Summary

Propofol, the recently marketed intravenous induction agent for anaesthesia, is chemically unrelated to earlier anaesthetic drugs. This highly lipophilic agent has a fast onset and short, predictable duration of action due to its rapid penetration of the blood-brain barrier and distribution to the CNS, followed by redistribution to inactive tissue depots such as muscle and fat. On the basis of pharmacokinetic-pharmacodynamic modelling, a mean blood-brain equilibration half-life of only 2.9 minutes has been calculated.

In most studies, the blood concentration curve of propofol has been best fitted to a 3-compartment open model, although in some patients only 2 exponential phases can be defined. The first exponential phase half-life of 2 to 3 minutes mirrors the rapid onset of action, the second (34 to 56 minutes) that of the high metabolic clearance, whereas the long third exponential phase half-life of 184 to 480 minutes describes the slow elimination of a small proportion of the drug remaining in poorly perfused tissues. Thus, after both a single intravenous injection and a continuous intravenous infusion, the blood concentrations rapidly decrease below those necessary to maintain sleep (around 1 mg/L), based on both the rapid distribution, redistribution and metabolism during the first and second exponential phases (more than 70% of the drug is eliminated during these 2 phases). During long term intravenous infusions cumulative drug concentrations and effects might be expected, but even then the recovery times do not appear to be much delayed.

The liver is probably the main eliminating organ, and renal clearance appears to play little part in the total clearance of propofol. On the other hand, because the total body clearance may exceed liver blood flow, an extrahepatic metabolism or extrarenal elimination (e.g. via the lungs) has been suggested. Approximately 60% of a radiolabelled dose of propofol is excreted in the urine as 1- and 4-glucuronide and 4-sulphate conjugates of 2,6-diisopropyl 1,4-quinol, and the remainder consists of the propofol glucuronide.

Thus for hepatic and renal diseases, co-medication, surgical procedure, gender and obesity do not appear to cause clinically significant changes in the pharmacokinetic profile of propofol, but the decrease in the clearance value in the elderly might produce higher concentrations during a long term infusion, with an increased drug effect. In addition, the lower induction dose observed in relation to increased age might be partly explained by a smaller central volume of distribution.

Interestingly, the concentration-effect relationship of propofol appears to be much less variable between individuals than are its disposition kinetics. At the onset of unconsciousness mean blood concentration of around 6 to 10 mg/L is needed, but during maintenance of anaesthesia much lower levels of around 2 to 4 mg/L are effective. A good correlation between EEG activity and blood propofol concentrations has been reported. Importantly, a clear hysteresis in concentration-effect studies has been found with higher blood propofol concentrations at the onset of unconsciousness than are necessary to maintain sleep.

Propofol has a unique pharmacokinetic profile, a knowledge of which may improve the understanding of its pharmacodynamic properties. Despite a very long terminal half-life related to a high volume of distribution, recovery from propofol is short and predictable due to the relative importance of distribution rates and elimination. Moreover, the good concentration-effect relationship with a low individual variability is of great clinical significance.

Keywords

Halothane Alfentanil Hepatic Blood Flow Postgraduate Medical Journal Disposition Kinetic 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Adam HK, Briggs LP, Bahar M, Douglas EJ, Dundee JW. Pharmacokinetic evaluation of ICI 35868 in man. Single induction doses with different rates of injection. British Journal of Anaesthesia 55: 97–103, 1983PubMedCrossRefGoogle Scholar
  2. Adam HK, Douglas EJ, Plummer GF, Cosgrove MB. Estimation of ICI 35868 (Diprivan) in blood by high performance liquid chromatography, following coupling with Gibb’s reagent. Journal of Chromatography 223: 232, 1981PubMedCrossRefGoogle Scholar
  3. Adam HK, Kay B, Douglas EJ. Blood disoprofol levels in anaesthetised patients. Correlation of concentrations after single or repeated doses with hypnotic activity. Anaesthesia 37: 536–540, 1982PubMedCrossRefGoogle Scholar
  4. Albanèse J, Auffray JP, Lacarelle B, Martin C, Gouin F. Pharmacokinetics of propofol administered by continuous intravenous infusion in man. Anesthesiology 67: A667, 1987CrossRefGoogle Scholar
  5. Arden JR, Holley FO, Stanski DR. Increased sensitivity to etomidate in the elderly. Initial distribution versus altered brain response. Anesthesiology 65: 19–27, 1986PubMedCrossRefGoogle Scholar
  6. Bell JP, Pottecker T, Mangin P, Fratte C, Otteni JC. Sédation prolongée par le propofol en reánimation. Résultats préliminaires. Annales Françaises d’Anesthésie et de Réanimation 6: 334–335, 1987CrossRefGoogle Scholar
  7. Camu F, Gepts E, Cockshott ID, Douglas EJ. Dose response curves and elimination kinetics following infusions of 3, 6 and 9 mg/kg/h Diprivan. Proceedings of the Industry Forum. Propofol (Diprivan) infusion techniques for intravenous sedation or maintenance of anaesthesia, pp. 14–17, VII European Congress of Anaesthesiology, Vienna, 1986Google Scholar
  8. Christensen JH, Andreasen F, Jansen JA. Pharmacokinetics and pharmacodynamics of thiopentone. A comparison between young and elderly patients. Anaesthesia 37: 398–404, 1982PubMedCrossRefGoogle Scholar
  9. Cockshott ID. Propofol (‘Diprivan’) pharmacokinetics and metabolism — an overview. Postgraduate Medical Journal 61 (Suppl. 3): 45–50, 1985PubMedGoogle Scholar
  10. Cockshott ID, Briggs LP, Douglas EJ, White M. Pharmacokinetics of propofol in female patients. Studies using single bolus injections. British Journal of Anaesthesia 59: 1103–1110, 1987aPubMedCrossRefGoogle Scholar
  11. Cockshott ID, Douglas EJ, Prys-Roberts C, Turtle M, Coates DP. Pharmacokinetics of propofol during and after i.v. infusion in man. British Journal of Anaesthesia 59: 941P–942P, 1987bCrossRefGoogle Scholar
  12. Doze VA, Shafer A, White PF. Propofol blood concentrations required to supplement nitrous oxide anesthesia. Anesthesia and Analgesia 67: S51, 1988CrossRefGoogle Scholar
  13. Dundee JW, Robinson FP, McCollum JSC, Patterson CC. Sensitivity to propofol in the elderly. Anaesthesia 41: 482–485, 1986PubMedCrossRefGoogle Scholar
  14. Elfström J. Drug pharmacokinetics in the postoperative period. Clinical Pharmacokinetics 4: 16–38, 1979PubMedCrossRefGoogle Scholar
  15. George CF. Drug kinetics and hepatic blood flow. Clinical Pharmacokinetics 4: 433–448, 1979PubMedCrossRefGoogle Scholar
  16. Gepts E, Camu F, Cockshott ID, Douglas EJ. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesthesia and Analgesia 66: 1256–1263, 1987PubMedCrossRefGoogle Scholar
  17. Gepts E, Jonckheer K, Maes V, Sonck W, Camu F. Disposition kinetics of propofol during alfentanil anaesthesia. Anaesthesia 43 (Suppl.): 8–13, 1988PubMedCrossRefGoogle Scholar
  18. Ghoneim MM, Korttila K. Pharmacokinetics of intravenous anaesthetics. Implications for clinical use. Clinical Pharmacokinetics 2: 344–372, 1977PubMedCrossRefGoogle Scholar
  19. Glen JB, Hunter SC. The pharmacology of an emulsion formulation of ICI 35868 (Diprivan). British Journal of Anaesthesia 56: 617–626, 1984PubMedCrossRefGoogle Scholar
  20. Hazeaux C, Tisserant D, Vespignani H, Hummer-Siegel M, Kwan-Ning V, et al. Retentissement électroencéphalographique de l’anethésie au propofol. Annales Françaises d’Anesthésie et de Réanimation 6: 261–266, 1987PubMedCrossRefGoogle Scholar
  21. Herregods L, Rolly G, Bogaert M. EEG and EMG monitoring during propofol induction and maintenance of anaesthesia. International Journal of Clinical Monitoring and Computing, in press, 1989Google Scholar
  22. Herregods L, Rolly G, Versichelen L, Rosseel MT. Propofol combined with nitrous oxide-oxygen for induction and maintenance of anaesthesia. Anaesthesia 42: 360–365, 1987PubMedCrossRefGoogle Scholar
  23. Homer TD, Stanski DR. The effect of increasing age on thiopental disposition and anesthetic requirement. Anesthesiology 62: 714–724, 1985PubMedCrossRefGoogle Scholar
  24. Kanto JH. Propofol, the newest induction agent of anesthesia. International Journal of Clinical Pharmacology, Therapy and Toxicology 26: 41–57, 1988Google Scholar
  25. Kanto J, Klotz U. Intravenous benzodiazepines as anaesthetic agents. Pharmacokinetics and clinical consequences. Acta Anaesthesiologica Scandinavica 26: 554–569, 1982PubMedCrossRefGoogle Scholar
  26. Kanto J, Valtonen M, Rosenberg P. Comparison of propofol and thiopentone for induction of anaesthesia in elective caesarean section. Anaesthesia, in press, 1989Google Scholar
  27. Kay NH, Sear JW, Uppington J, Cockshott ID, Douglas EJ. Disposition of propofol in patients undergoing surgery. A comparison in men and women. British Journal of Anaesthesia 58: 1075–1079, 1986PubMedCrossRefGoogle Scholar
  28. Kay NH, Stephenson DK. Dose-response relationship for disoprofol (ICI 35868, Diprivan). Comparison with methohexitone. Anaesthesia 36: 863–867, 1981PubMedCrossRefGoogle Scholar
  29. Kay NH, Uppington J, Sear JW, Douglas EJ, Cockshott ID. Pharmacokinetics of propofol (Diprivan) as an induction agent. Postgraduate Medical Journal 61 (Suppl. 3): 55–57, 1985PubMedGoogle Scholar
  30. Kirkpatrick T, Cockshott ID, Douglas EJ, Nimmo WS. Pharmacokinetics of propofol (Diprivan) in elderly patients. British Journal of Anaesthesia 60: 146–150, 1988PubMedCrossRefGoogle Scholar
  31. Knell PJW, McKean JF. An investigation of the pharmacokinetic profile of propofol (Diprivan) after administration for induction and maintenance of anaesthesia by repeat bolus doses in patients having spinal anaesthetic block. Postgraduate Medical Journal 61 (Suppl. 3): 60–61, 1985PubMedGoogle Scholar
  32. Landais A, Cockshott ID, Coppens MC, Cohn N, Richard MD, et al. Pharmacocinétique du propofol comme agent d’induction chez l’adulte. Cahiers d’Anesthésiologie 35: 427–428, 1987PubMedGoogle Scholar
  33. Langley MS, Heel RC. Propofol. A review of its pharmacokinetic properties and use as an intravenous anaesthetic. Drugs 35: 334–372, 1988PubMedCrossRefGoogle Scholar
  34. Leithe ME, Hermiller JB, Magorien RD, Unverferth DV, Leier CV. The effect of age on central and regional haemodynamics. Gerontology 30: 240–246, 1984PubMedCrossRefGoogle Scholar
  35. Major E, Aun C, Yate PM, Savege TM, Verniquet AJW, et al. Influence of sample site on blood concentrations of ICI 35868. British Journal of Anaesthesia 55: 371–375, 1983PubMedCrossRefGoogle Scholar
  36. Moore RG, McBride WG. The disposition kinetics of diazepam in pregnant women. European Journal of Clinical Pharmacology 13: 275–280, 1978PubMedCrossRefGoogle Scholar
  37. Morcos WE, Payne JP. The induction of anaesthesia with propofol (‘Diprivan’) compared in normal and renal failure patients. Postgraduate Medical Journal 61 (Suppl. 3): 62–63, 1985PubMedGoogle Scholar
  38. Morgan DJ, Blackman GL, Pauli JD, Wolff LJ. Pharmacokinetics and plasma binding of thiopental. II. Studies at cesarean section. Anesthesiology 54: 474–479, 1981PubMedCrossRefGoogle Scholar
  39. Nies AS, Shand DG, Wilkinson GR. Altered hepatic blood flow and drug disposition. Clinical Pharmacokinetics 1: 135–155, 1976PubMedCrossRefGoogle Scholar
  40. Orko R, Rosenberg PH, Himberg J-J. Intravenous infusion of midazolam, propofol and vecuronium in a patient with severe tetanus. Acta Anaesthesiologica Scandinavica 32: 590–592, 1988PubMedCrossRefGoogle Scholar
  41. Roberts FL, Dixon J, Lewis GTR, Prys-Roberts C, Harvey JR. A manually-controlled infusion scheme for propofol. British Journal of Anaesthesia 60: 342P, 1988Google Scholar
  42. Rolly G, Versichelen L, Huyghe L, Mungroop H. Effect of speed of injection on induction of anaesthesia with propofol. British Journal of Anaesthesia 57: 743–746, 1985PubMedCrossRefGoogle Scholar
  43. Schüttler J, Kloos S, Schwilden H, Stoeckel H. Total intravenous anaesthesia with propofol and alfentanil by computer-assisted infusion. Anaesthesia 43 (Suppl.): 2–7, 1988PubMedCrossRefGoogle Scholar
  44. Schüttler J, Schwilden H, Stoeckel H. Pharmacokinetic-dynamic modelling of diprivan. Anesthesiology 65: A549, 1986CrossRefGoogle Scholar
  45. Schüttler J, Stoeckel H, Schwilden H. Pharmacokinetic and pharmacodynamic modelling of propofol (‘Diprivan’) in volunteers and surgical patients. Postgraduate Medical Journal 61: 53–54, 1985PubMedCrossRefGoogle Scholar
  46. Scott JC, Stanski DR. Decreased fentanyl and alfentanil dose requirements with increasing age. A pharmacodynamic basis. Anesthesiology 63: A37, 1985CrossRefGoogle Scholar
  47. Servin F, Desmonts JM, Farinotti R, Haberer JP, Winckler C. Pharmacocinétique du propofol en perfusion continue chez le cirrhotique. Résultats préliminaires. Annales Françaises d’Anesthésie et de Réanimation 6: 228–229, 1987PubMedCrossRefGoogle Scholar
  48. Servin F, Haberer JP, Cockshott ID, Farinotti R, Desmonts JM. Propofol pharmacokinetics in patients with cirrhosis. Anesthesiology 65: A554, 1986CrossRefGoogle Scholar
  49. Shafer A, Doze VA, Shafer S, White PF. Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia. Anesthesiology 69: 348–356, 1988PubMedCrossRefGoogle Scholar
  50. Simons PJ, Cockshott ID, Douglas EJ, Gordon EA, Hopkins K, et al. Bood concentrations, metabolism and elimination after a subanaesthetic intravenous dose of 14C-propofol (‘Diprivan’) to male volunteers. Postgraduate Medical Journal 61 (Suppl. 3): 64, 1985Google Scholar
  51. Simons PJ, Cockshott ID, Douglas EJ, Gordon EA, Hopkins K, et al. Disposition in male volunteers of a subanaesthetic intravenousc dose of an oil in water emulsion of 14C-propofol. Xenobiotica 18: 429–440, 1988PubMedCrossRefGoogle Scholar
  52. Spelina KR, Coates DP, Monk CR, Prys-Roberts C, Norley I, et al. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. I. Patients premedicated with morphine sulphate. British Journal of Anaesthesia 58: 1080–1084, 1986PubMedCrossRefGoogle Scholar
  53. Turtle MJ, Cullen P, Prys-Roberts C, Coates D, Monk CR, et al. Dose requirements of propofol by infusion during nitrous oxide anaesthesia in man. II. Patients premedicated with lorazepam. British Journal of Anaesthesia 59: 283–287, 1987PubMedCrossRefGoogle Scholar
  54. Valtonen M, Iisalo E, Kanto J, Rosenberg P. Propofol as an induction agent in children: pain on injection and pharmacokinetics. Acta Anaesthesiologica Scandinavica 33: 152–155, 1989PubMedCrossRefGoogle Scholar
  55. Vandesteene A, Trempont V, Deloof T, Engelman E, Wathieu JP, et al. Influence of propofol on EEG. Abstract, p.163. Proceedings of the 5th International Congress of the Belgian Society of Anesthesia and Reanimation, Brussels, 1988Google Scholar
  56. White PF. Propofol: pharmacokinetics and pharmacodynamics. Seminars in Anaesthesia 7: 4–20, 1988Google Scholar
  57. Vinik HR, Shaw B, MacKrell T, Hughes G. Diprivan compared with methohexitone or isoflurane for maintenance of anaesthesia. Proceedings of the Industry Forum. Propofol (Diprivan) infusion techniques for intravenous sedation and maintenance of anaesthesia, pp 46–48, VII European Congress of Anaesthesiology, Vienna, 1986Google Scholar

Copyright information

© ADIS Press Limited 1989

Authors and Affiliations

  • J. Kanto
    • 1
    • 2
  • E. Gepts
    • 1
    • 2
  1. 1.Departments of Anaesthesiology and Clinical PharmacologyUniversity of TurkuTurkuFinland
  2. 2.Department of AnaesthesiologyFlemish Free University of BrusselsBrusselsBelgium

Personalised recommendations