Journal of Pharmacokinetics and Biopharmaceutics

, Volume 22, Issue 5, pp 381–410 | Cite as

Comparative physiological pharmacokinetics of fentanyl and alfentanil in rats and humans based on parametric single-tissue models

  • Sven Björkman
  • D. Russell Wada
  • Donald R. Stanski
  • William F. Ebling


The objectives of this investigation were to characterize the disposition of fentanyl and alfentanil in 14 tissues in the rat, and to create physiological pharmacokinetic models for these opioids that would be scalable to man. We first created a parametric submodel for the disposition of either drug in each tissue and then assembled these submodels into whole-body models. The disposition of fentanyl and alfentanil in the heart and brain and of fentanyl in the lungs could be described by perfusion-limited 1-compartment models. The disposition of both opioids in all other examined tissues was characterized by 2- or 3-compartment models. From these models, the extraction ratios of the opioids in the various tissues could be calculated, confirming the generally lower extraction of alfentanil as compared to fentanyl. Assembly of the single-tissue models resulted in a whole-body model for fentanyl that accurately described its disposition in the rat. A similar assembly of the tissue models for alfentanil revealed non-first-order elimination kinetics that were not apparent in the blood concentration data. Michaelis-Menten parameters for the hepatic metabolism of alfentanil were determined by iterative optimization of the entire model. The parametric models were finally scaled to describe the disposition of fentanyl and alfentanil in humans.

Key words

fentanyl alfentanil physiological models regional blood flow tissue distribution tissue diffusion rats humans 


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  1. 1.
    J. L. Gabrielsson, P. Johansson, U. Bondesson, and L. K. Paalzow. Analysis of methadone disposition in the pregnant rat by means of a physiological flow model.J. Pharmacokin. Biopharm. 13:355–372 (1985).CrossRefGoogle Scholar
  2. 2.
    J. L. Gabrielsson and T. Groth. An extended physiological pharmacokinetic model of methadone disposition in the rat: validation and sensitivity analysis.J. Pharmacokin. Biopharm. 16:183–201 (1988).CrossRefGoogle Scholar
  3. 3.
    J. L. Gabrielsson, P. Johansson, U. Bondesson, M. Karlsson, and L. K. Paalzow. Analysis of pethidine disposition in the pregnant rat by means of a physiological flow model.J. Pharmacokin. Biopharm. 14:381–395 (1986).CrossRefGoogle Scholar
  4. 4.
    S. Björkman, D. R. Stanski, D. Verotta, and H. Harashima. Comparative tissue concentration profiles of fentanyl and alfentanil in humans predicted from tissue/blood partition data obtained in rats.Anesthesiology 72:865–873 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    N. R. Davis and W. W. Mapleson. A physiological model for the distribution of injected agents, with special reference to pethidine.Br. J. Anaesth. 70:248–258 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    K. B. Bischoff. Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.Cancer Chemother. Rep. 59:777–793 (1975).PubMedGoogle Scholar
  7. 7.
    R. J. Lutz, R. L. Dedrick, and D. S. Zaharko. Physiological pharmacokinetics: anin vivo approach to membrane transport.Pharmacol. Ther. 11:559–592 (1980).PubMedCrossRefGoogle Scholar
  8. 8.
    L. E. Gerlowski and R. K. Jain. Physiologically based pharmacokinetic modeling: principles and applications.J. Pharm. Sci. 72:1103–1127 (1983).PubMedCrossRefGoogle Scholar
  9. 9.
    S. Björkman, D. R. Stanski, H. Harashima, R. Dowrie, S. R. Harapat, D. R. Wada, and W. F. Ebling. Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model.J. Pharmacokin. Biopharm. 21:255–279 (1993).CrossRefGoogle Scholar
  10. 10.
    F. G. King and R. L. Dedrick. Physiologic model for the pharmacokinetics of 2′-deoxycoformycin in normal and leukemic mice.J. Pharmacokin. Biopharm. 9:519–534 (1981).CrossRefGoogle Scholar
  11. 11.
    M. J. Angelo, K. B. Bischoff, A. B. Pritchard, and M. A. Presser. A physiological model for the pharmacokinetics of methylene chloride in B6C3F1 mice following intravenous administrations.J. Pharmacokin. Biopharm. 12:413–436 (1984).CrossRefGoogle Scholar
  12. 12.
    J. M. Gallo, P. Varkonyi, E. E. Hassan, and D. R. Groothius. Targeting anticancer drugs to the brain: II. Physiological pharmacokinetic model of oxantrazole following intraarterial administration to rat glioma-2 (RG-2) bearing rats.J. Pharmacokin. Biopharm. 21:575–592 (1993).CrossRefGoogle Scholar
  13. 13.
    W. F. Ebling, D. R. Wada, and D. R. Stanski. From piecewise to full physiologic pharmacokinetic modeling: applied to thiopental disposition in the rat.J. Pharmacokin. Biopharm. 22:259–292 (1994).CrossRefGoogle Scholar
  14. 14.
    S. Björkman and D. R. Stanski. Simultaneous determination of fentanyl and alfentanil in rat tissues by capillary column gas chromatography.J. Chromatog. 433:95–104 (1988).CrossRefGoogle Scholar
  15. 15.
    D. Z. D'Argenio and A. Schumitzky. A program package for simulation and parameter estimation in pharmacokinetic systems.Comput. Prog. Biomed. 9:115–134 (1979).CrossRefGoogle Scholar
  16. 16.
    L. R. Williams and R. W. Leggett. Reference values for resting blood flow to organs of man.Clin. Phys. Physiol. Meas. 10:187–217 (1989).PubMedCrossRefGoogle Scholar
  17. 17.
    N. B. Everett, B. Simmons, and E. P. Lasher. Distribution of blood (Fe59) and plasma (I131) volumes of rats determined by liquid nitrogen freezing.Circ. Res. 4:419–424 (1956).PubMedCrossRefGoogle Scholar
  18. 18.
    D. R. Wada, D. R. Stanski, and W. F. Ebling. A PC-based graphical simulator for physiological pharmacokinetic models.Comput. Meth Prog. Biomed. (in press).Google Scholar
  19. 19.
    K. Yamaoka, T. Nakagawa, and T. Uno. Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations.J. Pharmacokin. Biopharm. 6:165–175 (1978).CrossRefGoogle Scholar
  20. 20.
    K. Taeger, E. Weninger, F. Schmelzer, M. Adt, N. Franke, and K. Peter. Pulmonary kinetics of fentanyl and alfentanil in surgical patients.Br. J. Anaesth. 61:425–434 (1988).PubMedCrossRefGoogle Scholar
  21. 21.
    F. Boer, J. G. Bovill, A. G. L. Burm, and R. A. G. Mooren. Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery.Br. J. Anaesth. 68:370–375 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    J. R. Varvel, S. L. Shafer, S. S. Hwang, P. A. Coen, and D. R. Stanski. Absorption characteristics of transdermally administered fentanyl.Anesthesiology 70:928–934 (1989).PubMedCrossRefGoogle Scholar
  23. 23.
    H. J. M. Lemmens, J. B. Dyck, S. L. Shafer, and D. R. Stanski. Pharmacokinetic/dynamic modeling in drug development: Application to the investigational opioid trefentanil.Clin. Pharmacol. Ther. 56:261–271 (1994).PubMedCrossRefGoogle Scholar
  24. 24.
    W. E. G. Meuldermans, R. M. A. Hurkmans, and J. J. P. Heykants. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood.Arch. int. Pharmacodyn. 257:4–19 (1982).PubMedGoogle Scholar
  25. 25.
    M. Yaster, R. C. Koehler, and R. J. Traystman, Effects of fentanyl on peripheral and cerebral hemodynamics in neonatal lambs.Anesthesiology 66:524–530 (1987).PubMedCrossRefGoogle Scholar
  26. 26.
    N. D. Kien, J. A. Reitan, D. A. White, C-H. Wu, and J. H. Eisele. Hemodynamic responses to alfentanil in halothane-anesthetized dogs.Anesth. Analg. 65:765–770 (1986).PubMedCrossRefGoogle Scholar
  27. 27.
    S. S. Kety. The theory and applications of the exchange of inert gas at the lungs and tissues.Pharmacol. Rev. 3:1–40 (1951).PubMedGoogle Scholar
  28. 28.
    S. Björkman, J. Åkeson, F. Nilsson, K. Messeter, and B. Roth. Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: An application of mass balance pharmacokinetics with a changing regional blood flow.J. Pharmacokin. Biopharm. 20:637–652 (1992).CrossRefGoogle Scholar
  29. 29.
    J. D. Horowitz, M. K. Dynon, E. Woodward, S. T. B. Sia, P. S. MacDonald, D. J. Morgan, A. J. Globe, and W. J. Louis. Short-term myocardial uptake of lidocaine and mexiletine in patients with ischemic heart disease.Circulation 73:987–996 (1986).PubMedCrossRefGoogle Scholar
  30. 30.
    Y. F. Huang, R. N. Upton, and W. B. Runciman. I.V. bolus administration of subconvulsive doses of lignocaine to conscious sheep: Myocardial pharmacokinetics.Br. J. Anaesth. 70:326–332 (1993).PubMedCrossRefGoogle Scholar
  31. 31.
    G. P. Stec and A. J. Atkinson. Analysis of the contributions of permeability and flow to intercompartmental clearance.J. Pharmacokin. Biopharm. 9:167–180 (1981).CrossRefGoogle Scholar
  32. 32.
    D. L. Roerig, K. J. Kotrly, E. J. Vucins, S. B. Ahlf, C. A. Dawson, and J. P. Kampine. First pass uptake of fentanyl, meperidine, and morphine in the human lung.Anesthesiology 67:466–472 (1987)PubMedCrossRefGoogle Scholar
  33. 33.
    D. L. Roerig, K. J. Kotrly, S. B. Ahlf, C. A.Dawson, and J. P. Kampine. Effect of propranolol on the first pass uptake of fentanyl in the human and rat lung.Anesthesiology 71:62–68 (1989).PubMedCrossRefGoogle Scholar
  34. 34.
    R. Hess, A. Herz, and K. Friedel. Pharmacokinetics of fentanyl in rabbits in view of the importance for limiting the effect.J. Pharmacol. Exp. Ther. 179:474–484 (1971).PubMedGoogle Scholar
  35. 35.
    C. C. Hug and M. R. Murphy. Tissue redistribution of fentanyl and termination of its effects in rats.Anesthesiology,55:369–375 (1981).PubMedCrossRefGoogle Scholar
  36. 36.
    K. A. Lehmann, L. Hunger, K. Brandt, and D. Daub. Biotransformation von Fentanyl.Anaesthetist 32:165–173 (1983).Google Scholar
  37. 37.
    E. Schneider and K. Brune. Distribution of fentanyl in rats: an autoradiographic study.Naunyn-Schmiedebergs Arch. Pharmacol. 331:359–363 (1985).PubMedCrossRefGoogle Scholar
  38. 38.
    H. Stoeckel, J. H. Hengstmann, and J. Schüttler. Pharmacokinetics of fentanyl as a possible explanation for recurrence of respiratory depression.Br. J. Anaesth. 51:741–745 (1979).PubMedCrossRefGoogle Scholar
  39. 39.
    L. B. Sheiner. Analysis of pharmacokinetic data using parametric models. II. Point estimates of an individual's parameters.J. Pharmacokin. Biopharm. 13:515–540 (1985).CrossRefGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Sven Björkman
    • 1
    • 2
  • D. Russell Wada
    • 2
  • Donald R. Stanski
    • 2
  • William F. Ebling
    • 3
  1. 1.Hospital PharmacyMalmö General HospitalMalmöSweden
  2. 2.Department of AnesthesiaStanford University School of MedicineStanford
  3. 3.Department of Pharmaceutics, School of PharmacyState University of New YorkBuffalo

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