Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients

  • Michael WeissEmail author
  • Marije Reekers
  • Jaap Vuyk
  • Fred Boer


The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89 min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16 l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.


Rocuronium Circulatory pharmacokinetic model Distribution kinetics ICG Cardiac output Transit time dispersion 


  1. 1.
    Kuipers JA, Boer F, Olofsen E, Bovill JG, Burm AGL (2001) Recirculatory pharmacokinetics and pharmacodynamics of rocuronium in patients: the influence of cardiac output. Anesthesiology 94:47–55PubMedCrossRefGoogle Scholar
  2. 2.
    Henthorn TK, Krejcie TC, Avram MJ (2008) Early drug distribution: a generally neglected aspect of pharmacokinetics of particular relevance to intravenously administered anesthetic agents. Clin Pharmacol Ther 84:18–22PubMedCrossRefGoogle Scholar
  3. 3.
    Weiss M, Roberts MS (1996) Tissue distribution kinetics as determinant of transit time dispersion of drugs in organs: application of a stochastic model to the rat hindlimb. J Pharmacokinet Pharmacodyn 24:173–196Google Scholar
  4. 4.
    Weiss M, Krejcie TC, Avram MJ (2007) Circulatory transport and capillary-tissue exchange as determinants of the distribution kinetics of inulin and antipyrine in dog. J Pharm Sci 96:913–926PubMedCrossRefGoogle Scholar
  5. 5.
    Weiss M, Krejcie TC, Avram MJ (2007) A minimal physiological model of thiopental distribution kinetics based on a multiple indicator approach. Drug Metab Dispos 35:1525–1532PubMedCrossRefGoogle Scholar
  6. 6.
    Weiss M (2009) Cardiac output and systemic transit time dispersion as determinants of circulatory mixing time: a simulation study. J Appl Physiol 107:445–449PubMedCrossRefGoogle Scholar
  7. 7.
    Olofsen E, Dahan A (2005) Population pharmacokinetics/pharmacodynamics of anesthetics. AAPS J 7:E383–E389PubMedCrossRefGoogle Scholar
  8. 8.
    Weiss M (2007) Residence time dispersion as a general measure of drug distribution kinetics: Estimation and physiological interpretation. Pharm Res 24:2025–2030PubMedCrossRefGoogle Scholar
  9. 9.
    D’Argenio DZ, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: pharmacokinetic/pharmacodynamic systems analysis software. Biomedical Simulations Resource, Los AngelesGoogle Scholar
  10. 10.
    Weiss M, Krejcie TC, Avram MJ (2006) Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity. Am J Physiol Heart Circ Physiol 291:H861–H870PubMedCrossRefGoogle Scholar
  11. 11.
    Messerli FH, De Carvalho JG, Christie B, Frohlich ED (1978) Systemic and regional hemodynamics in low, normal and high cardiac output borderline hypertension. Circulation 58:441–448PubMedGoogle Scholar
  12. 12.
    Ulrych M, Frohlich ED, Tarazi RC, Dustan HP, Page IH (1969) Cardiac output and distribution of blood volume in central and peripheral circulations in hypertensive and normotensive man. Br Heart J 31:570–574PubMedCrossRefGoogle Scholar
  13. 13.
    Zavorsky GS, Walley KR, Russell JA (2003) Red cell pulmonary transit times through the healthy human lung. Exp Physiol 88:191–200PubMedCrossRefGoogle Scholar
  14. 14.
    Rocca GD, Costa MG, Pietropaoli P (2007) How to measure and interpret volumetric measures of preload. Curr Opin Crit Care 13:297–302PubMedCrossRefGoogle Scholar
  15. 15.
    Heinonen I, Kemppainen J, Kaskinoro K, Peltonen JE, Borra R, Lindroos MM, Oikonen V, Nuutila P, Knuuti J, Hellsten Y, Boushel R, Kalliokoski KK (2010) Comparison of exogenous adenosine and voluntary exercise on human skeletal muscle perfusion and perfusion heterogeneity. J Appl Physiol 108:378–386PubMedCrossRefGoogle Scholar
  16. 16.
    Presson RG Jr, Hanger CC, Godbey PS, Graham JA, Lloyd TC Jr, Wagner WW Jr (1994) Effect of increasing flow on distribution of pulmonary capillary transit times. J Appl Physiol 76:1701–1711PubMedCrossRefGoogle Scholar
  17. 17.
    Capderou A, Douguet D, Similowski T, Aurengo A, Zelter M (1997) Non-invasive assessment of technetium-99m albumin transit time distribution in the pulmonary circulation by first-pass angiocardiography. Eur J Nucl Med 24:745–753PubMedGoogle Scholar
  18. 18.
    Wynne HA, Goudevenos J, Rawlins MD, James OF, Adams PC, Woodhouse KW (1990) Hepatic drug clearance: the effect of age using indocyanine green as a model compound. Br J Clin Pharmacol 30:634–637PubMedGoogle Scholar
  19. 19.
    Mertens MJ, Olofsen E, Burm AGL, Bovill JG, Vuyk J (2004) Mixed-effects modeling of the influence of alfentanil on propofol pharmacokinetics. Anesthesiology 100:795–805PubMedCrossRefGoogle Scholar
  20. 20.
    Lichtenbelt BJ, Olofsen E, Dahan A, van Kleef JW, Struys M, Vuyk J (2010) Propofol reduces the distribution and clearance of midazolam. Anesth Analg 110:1597–1606CrossRefGoogle Scholar
  21. 21.
    Bouillon T, Bruhn J, Radu-Radulescu L, Bertaccini E, Park S, Shafer S (2002) Non-steady state analysis of the pharmacokinetic interaction between propofol and remifentanil. Anesthesiology 97:1350–1362PubMedCrossRefGoogle Scholar
  22. 22.
    Nara E, Saikawa A, Masegi M, Hashida M, Sezaki H (1992) Contribution of interstitial diffusion in drug absorption from perfused rabbit muscle: effect of hyaluronidase on absorption. Chem Pharm Bull (Tokyo) 40:737–740Google Scholar
  23. 23.
    Ezzine S, Varin F (2005) Interstitial muscle concentrations of rocuronium under steady-state conditions in anaesthetized dogs: actual versus predicted values. Br J Anaesth 94:49–56PubMedCrossRefGoogle Scholar
  24. 24.
    Cameron KS, Fielding L (2002) NMR diffusion coefficient study of steroid-cyclodextrin inclusion complexes. Magn Reson Chem 40:S106–S109CrossRefGoogle Scholar
  25. 25.
    Paaske WP, Sejrsen P (1977) Transcapillary exchange of 14C-inulin by free diffusion in channels of fused vesicles. Acta Physiol Scand 100:437–445PubMedCrossRefGoogle Scholar
  26. 26.
    Keiding S, Henriksen O, Sejrsen P (1988) Muscle capillary permeability for [14C] inulin and [51Cr] EDTA in human forearm. Acta Physiol Scand 133:335–342PubMedCrossRefGoogle Scholar
  27. 27.
    Law RO, Phelps CF (1966) The size of the sucrose, raffinose, and inulin spaces in the gastrocnemius muscle in the rat. J Physiol 186:547–557PubMedGoogle Scholar
  28. 28.
    Weiss M, Hübner GH, Hübner IG, Teichmann W (1996) Effects of cardiac output on disposition kinetics of sorbitol: recirculatory modelling. Br J Clin Pharmacol 41:261–268PubMedCrossRefGoogle Scholar
  29. 29.
    Beaufort TM, Proost JH, Houwertjes MC, Roggeveld J, Wierda J (1999) The pulmonary first-pass uptake of five nondepolarizing muscle relaxants in the pig. Anesthesiology 90:477–483PubMedCrossRefGoogle Scholar
  30. 30.
    Levitt DG (2003) The pharmacokinetics of the interstitial space in humans. Clin Pharmacol 3:3Google Scholar
  31. 31.
    Avram MJ, Krejcie TC, Henthorn TK, Niemann CU (2004) Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution. J Pharmacol Exp Ther 311:617–624PubMedCrossRefGoogle Scholar
  32. 32.
    Schalla M, Weiss M (1999) Pharmacokinetic curve fitting using numerical inverse Laplace transformation. Eur J Pharm Sci 7:305–309PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Michael Weiss
    • 1
    Email author
  • Marije Reekers
    • 2
  • Jaap Vuyk
    • 2
  • Fred Boer
    • 2
  1. 1.Section of Pharmacokinetics, Department of PharmacologyMartin Luther University Halle-WittenbergHalle (Saale)Germany
  2. 2.Department of AnesthesiologyLeiden University Medical CentreLeidenThe Netherlands

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