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Drug Metabolism and Disposition Fast Forward
First published on May 30, 2007; DOI: 10.1124/dmd.106.014209

0090-9556/07/3509-1525-1532$20.00
DMD 35:1525-1532, 2007

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A Minimal Physiological Model of Thiopental Distribution Kinetics Based on a Multiple Indicator Approach

Michael Weiss, Tom C. Krejcie, and Michael J. Avram

Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany (M.W.); and Department of Anesthesiology and the Mary Beth Donnelley Clinical Pharmacology Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (T.C.K., M.J.A.)

Currently available models of thiopental disposition kinetics using only plasma concentration-time data neglect the influence of intratissue diffusion and provide no direct information on tissue partitioning in individual subjects. Our approach was based on a lumped-organ recirculatory model that has recently been applied to unbound compounds. The goal was to find the simplest model that accounts for the heterogeneity in tissue partition coefficients and accurately describes initial distribution kinetics of thiopental in dogs. To ensure identifiability of the underlying axially distributed capillary-tissue exchange model, simultaneously measured disposition data of the vascular indicator, indocyanine green, and the marker of whole body water, antipyrine, were analyzed together with those of thiopental. A model obtained by grouping the systemic organs in two subsystems containing fat and nonfat tissues, successfully described all data and allowed an accurate estimation of model parameters. The estimated tissue partition coefficients were in accordance with those measured in rats. Because of the effect of tissue binding, the diffusional equilibration time characterizing intratissue distribution of thiopental is longer than that of antipyrine. The approach could potentially be used in clinical pharmacokinetics and could increase our understanding of the effect of obesity on the disposition kinetics of lipid-soluble drugs.

Address correspondence to: Dr. Michael Weiss, Section of Pharmacokinetics, Department of Pharmacology, Martin Luther University Halle-Wittenberg, D-06097 Halle (Saale), Germany. E-mail: michael.weiss{at}medizin.uni-halle.de






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