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

Abstract

ABSTRACT: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.

Clinical Pharmacokinetic Applications of Recirculatory Models

“…From a physiological interpretation, a minimal recirculatory model including pulmonary and systemic circulation, as shown in Figure 2, has been proposed [15,22,23]. In this model, the basic equation for the arterial concentration-time curve for infinite cycles in a closed loop system for a vascular space marker such as ICG after a standard input may be expressed in the Laplace domain by the following equation:…”

“…Flow-limited distribution kinetics of drugs such as antipyrine or diffusion-limited distribution kinetics of substances such as inulin may be modelled [24]. In the advanced version of the model, the systemic organs are grouped into two subsystems, non-fat tissues and fat tissues [23].…”

Pharmacokinetic and Pharmacodynamic Principles for Intravenous Anesthetics

“…47 Model misspecification is important because anesthetics are often intended to exert their most profound effects very soon after a bolus is administered. [52][53][54][55] These more physiologically based PK modeling approaches have identified factors that influence anesthesia induction doses such as age, cardiac output, and concomitant use of drugs that alter cardiac function. 48,50,51 These limitations of compartmental models can be addressed with more complex "physiologic" and "recirculatory" models, although standard compartmental models are more commonly applied clinically despite their sometimes poor performance.…”

Anesthetic Pharmacology and the Morbidly Obese Patient

“…[27] Animal studies have demonstrated that distribution clearance of thiopental increases linearly with cardiac output. [28] With the increase in cardiac output associated with obesity, it is not surprising then that total clearance of thiopental is increased in obese vs. lean subjects. [26] There is no difference in thiopental clearance between obese and lean subjects when normalized to total body weight.…”