Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts

Abstract

Three advanced models of pharmacokinetics are described. In the fi rst class are physiologically based pharmacokinetic models based on in vitro data on transport and metabolism. The information is translated as transporter and enzyme activities and their attendant heterogeneities into liver and intestine models. Second are circulatory models based on transit time distribution and plasma concentration time curves. The third are fractal models for nonhomogeneous systems and non-Fickian processes are presented. The usefulness of these pharmacokinetic models, with examples, is compared.

Caco-2 cell monolayers as a tool to study simultaneous phase II metabolism and metabolite efflux of indomethacin, paracetamol and 1-naphthol

“…During the absorption from the gastrointestinal tract, a drug is exposed to several active barrier mechanisms, where the kinetics of the processes involved could limit the absorption or have a role in drug interactions. Several metabolic enzymes and efflux transporters are known to be functional in the enterocytes (Pang et al, 2007). In recent years, the interplay of these active processes has attracted a lot of research interest (Jeong et al, 2005).…”

Pharmacokinetics and Pharmacodynamics

“…Interpretation of pharmacokinetic data involves mathematical modeling to enable prediction of blood/ plasma and tissue concentrations time profiles, and facilitate mechanistic understanding of the underlying processes. It is widely recognized that these models currently used are vast oversimplifications "but we have to start somewhere" (Pang et al 2007).…”

“…Of the various approaches used to predict drug time profiles in the body, compartmental models are the simplest and most widely used (Pang et al 2007). The basis of the compartment model is equilibrium systems, homogeneity, and mass transfer between compartments.…”

“…Therefore, the system can be described by coupled first-order differential equations. Macheras and colleagues argue that the assumptions of homogeneity and wellstirred media are not supported by anatomical and physiological evidence (Macheras et al 1996;Macheras and Argyrakis 1997;Dokoumetzidis et al 2004;Pang et al 2007). …”

“…3), absorption (Macheras and Argyrakis 1997), and fractal compartment models (Fuite et al 2002;Marsh and Tuszynski 2006). Excellent reviews of these fractal concepts applied to pharmacokinetics have been published (Dokoumetzidis et al 2004;Pang et al 2007). …”