Comparison of distributed and compartmental models of drug disposition: assessment of tissue uptake kinetics

Abstract

The utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function. With a deviation in the estimate of the permeability-surface area product (PS) of about 18 %, the compartmental approach appears as a useful alternative on condition that a priori knowledge of cardiac output is included. It is also shown that the distribution clearance calculated from the parameters of a mammillary compartment model changes proportional to PS and can be used as an indirect measure of permeability-limited tissue uptake of drugs.

Unusual Distribution Kinetics of Gadoxetate in Healthy Human Subjects Genotyped for OATP1B1: Application of Population Analysis and a Minimal Physiological‐Based Pharmacokinetic Model

“…The differential equations are provided in Supplementary Materials. A similar model was previously used to analyze the disposition kinetics of rocuronium 13 and insulin 14 in humans. The adjustable model parameters k tp (tissue‐to‐plasma transport constant), PS (permeability‐surface area product), k in (uptake into hepatocytes), k out (sinusoidal back‐flux), and k e (excretion into bile) were estimated from the data.…”

An Open Source Patient Simulator for Design and Evaluation of Computer Based Multiple Drug Dosing Control for Anesthetic and Hemodynamic Variables

“…On a long term perspective, there is evidence to support the claim that assumption on homogeneous distribution and uptake kinetics of drug may be too optimistic [55], [56]. As a result, drug molecules may be trapped for longer residence times than initially though [53], with recirculatory effects from liver latency processing at macromolecular and metabolic rate dynamic variability [69].…”

“…However, this is not necessarily the case [51], [54]. It has been shown that slow acting compartments are more likely to have unbalanced clearance rates, therefore introducing a memory effect in the amount of drug acting on site [55]- [57], conceptually illustrated in Fig. 6.…”

A Minimal PKPD Interaction Model for Evaluating Synergy Effects of Combined NSCLC Therapies

“…On the other hand, the assumption of a kinetic rate constant for the probability of events is not fully correct, for it has internal states of switching information transcription following fractal patterns [53,54]. The immediate utility of such observations are the justification of assuming variations in tissue uptake dynamics [9]. The transit times of drug release and absorption are in power-law form, which are the basis for introducing fractional calculus in modelling pharmacokinetics [8].…”

“…Hill curve dose-effect dynamic variability can account for inter-and intra-patient variability [6,7]. Yet more, beyond the assumption of homogeneity in drug diffusion pattern in the body, fractal kinetics successfully characterized anomalous diffusion as a result of tissue heterogeneity in several applications with pharmacological data [8,9]. Latent response in drug therapy was assumed to be the result of drug trapping, leading to more accurate describing time-response of bolus administration [10,11].…”