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Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model

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Abstract

Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.

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References

  1. L. E. Mather. Clinical pharmacokinetics of fentanyl and its newer derivatives.Clin. Pharmacokin. 8:422–446 (1983).

    Article  CAS  Google Scholar 

  2. J. C. Scott and D. R. Stanski. Decreased fentanyl and alfentanil dose requirements with age. A simultaneous pharmacokinetic and pharmacodynamic evaluation.J. Pharmacol. Exp. Ther. 240:159–166 (1987).

    CAS  PubMed  Google Scholar 

  3. 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).

    Article  PubMed  Google Scholar 

  4. D. Verotta, L. B. Sheiner, W. F. Ebling, and D. R. Stanski. A semiparametric approach to physiological flow models.J. Pharmacokin. Biopharm. 17: 463–491 (1989).

    Article  CAS  Google Scholar 

  5. K. B. Bischoff. Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy.Cancer Chemother. Rep. 59:777–793 (1975).

    CAS  PubMed  Google Scholar 

  6. L. E. Gerlowski and R. K. Jain. Physiologically based pharmacokinetic modeling: Principles and applications.J. Pharm. Sci. 72:1103–1127 (1983).

    Article  CAS  PubMed  Google Scholar 

  7. K. J. Himmelstein and R. J. Lutz. A review of the applications of physiologically based pharmacokinetic modeling.J. Pharmacokin. Biopharm. 7:127–145 (1979).

    Article  CAS  Google Scholar 

  8. M. Rowland. Physiologic pharmacokinetic models: Relevance, experience and future trends.Drug Metab. Rev. 15:55–74 (1984).

    Article  CAS  PubMed  Google Scholar 

  9. S. Björkman and D. R. Stanski. Simultaneous determination of fentanyl and alfentanil in rat tissues by capillary column gas chromatography.J. Chromatogr. 433:95–104 (1988).

    Article  PubMed  Google Scholar 

  10. C. Long.Biochemists Handbook, Van Nostram, Princeton, NJ, 1968, p. 639.

    Google Scholar 

  11. N. Pace and D. F. Rahlmann. Estimation of skeletal muscle mass from body creatine content.Physiologist 25:S83-S84 (1982).

    Google Scholar 

  12. H. B. Waynforth.Experimental and Surgical Techniques in the Rat, Academic Press, London, 1980, p. 240.

    Google Scholar 

  13. S. F. Flaim, S. H. Nellis, E. J. Toggart, H. Drexler, K. Kanda, and E. D. Newman. Multiple simultaneous determinations of hemodynamics and flow distribution in the conscious rat.J. Pharmacol. Meth. 11:1–39 (1984).

    Article  CAS  Google Scholar 

  14. M. Gibaldi and D. Perrier.Pharmacokinetics, 2nd ed., Marcel Dekker, New York, 1982, pp. 45–109.

    Google Scholar 

  15. W. F. Ebling, E. N. Lee, and D. R. Stanski. Understanding pharmacokinetics and pharmacodynamics through computer simulation: I. The comparative clinical profiles of fentanyl and alfentanil.Anesthesiology 72:650–658 (1990).

    Article  CAS  PubMed  Google Scholar 

  16. D. Verotta. An inequality-constrained least-squares deconvolution method.J. Pharmacokin. Biopharm. 17:269–289 (1989).

    Article  CAS  Google Scholar 

  17. N. A. Lassen and W. Perl.Tracer Kinetic Methods in Medical Physiology, Raven Press, New York, 1979, pp. 76–99.

    Google Scholar 

  18. J. W. Mandema, P. Veng-Pedersen, and M. Danhof. Estimation of amobarbital plasma-effect site equilibration kinetics. Relevance of poly-exponential conductance functions.J. Pharmacokin. Biopharm. 19:617–634 (1991).

    Article  CAS  Google Scholar 

  19. N. B. Everett, B. Simmons, and E. P. Lasher. Distribution of blood (Fe59) and plasma (I131) volumes of rats determined by liquid nitrogen freezing.Circulation Res. 4:419–424 (1956).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Article  CAS  PubMed  Google Scholar 

  21. N. D. Kien, J. A. Reitan, D. A. White, C.-H. Wu, and J. H. Eisele. Hemodynamic responses to alfentanil in halothane-anesthetized dogs.Anest. Analg. 65:765–770 (1986).

    Article  CAS  Google Scholar 

  22. 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. Ther. 257:4–19 (1982).

    CAS  PubMed  Google Scholar 

  23. 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).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. 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. Parmacokin. Biopharm. 14:381–395 (1986).

    Article  CAS  Google Scholar 

  26. T. K. Henthorn, T. C. Krejcie, and M. J. Avram. The relationship between alfentanil distribution kinetics and cardiac output.Clin. Pharmacol. Ther. 52:190–196 (1992).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Hospital Pharmacy, Malmö General Hospital, S-21401, Malmö, Sweden

    Sven Björkman

  2. Veterans Administration Medical Center, Stanford University School of Medicine, Anesthesia Service, 94304, Palo Alto, California

    Donald R. Stanski, Robert Dowrie, Sandra R. Harapat, D. Russell Wada & William F. Ebling

  3. Faculty of Pharmaceutical Sciences, University of Tokushima, 1-78 Shomachi, 770, Tokushima, Japan

    Hideyoshi Harashima

Authors
  1. Sven Björkman
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  2. Donald R. Stanski
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  3. Hideyoshi Harashima
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  4. Robert Dowrie
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  5. Sandra R. Harapat
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  6. D. Russell Wada
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  7. William F. Ebling
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Additional information

Supported in part by the National Institute on Aging, RO1-AG-4594, the Anesthesia/ Pharmacology Research Foundation, and a travel grant from Janssen Pharma AB (Sweden).

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Björkman, S., Stanski, D.R., Harashima, H. et al. Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model. Journal of Pharmacokinetics and Biopharmaceutics 21, 255–279 (1993). https://doi.org/10.1007/BF01059779

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  • DOI: https://doi.org/10.1007/BF01059779

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