Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients
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.
KeywordsRocuronium Circulatory pharmacokinetic model Distribution kinetics ICG Cardiac output Transit time dispersion
- 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
- 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
- 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
- 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
- 30.Levitt DG (2003) The pharmacokinetics of the interstitial space in humans. Clin Pharmacol 3:3Google Scholar