PT  - JOURNAL ARTICLE
AU  - Michael Weiss
AU  - Tom C. Krejcie
AU  - Michael J. Avram
TI  - A Minimal Physiological Model of Thiopental Distribution Kinetics Based on a Multiple Indicator Approach
AID  - 10.1124/dmd.106.014209
DP  - 2007 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1525--1532
VI  - 35
IP  - 9
4099  - http://dmd.aspetjournals.org/content/35/9/1525.short
4100  - http://dmd.aspetjournals.org/content/35/9/1525.full
SO  - Drug Metab Dispos2007 Sep 01; 35
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics