Effects of pharmaceuticals and other active chemicals at biological targets: mechanisms, interactions, and integration into PB-PK/PD models

Abstract

Biologically active molecules, that is pharmaceuticals and other chemical substances, exert their therapeutic and/or toxic effects by complex interactions with their biological targets/active sites. This review discusses the factors and processes governing the kinetics and effects of active molecules at their cellular targets, the chain of events leading to clinical effects, and the crosstalk between regulatory pathways controlling these processes. Special attention is given to the discussion of effects of a single drug or other chemical on multiple targets, to the interaction of multiple ligands with a single target/receptor and the effects of single ligand–target complexes on multiple signal transduction pathways, and to the control of physiological functions, such as regulation of blood glucose levels, by numerous primary mechanisms acting on different cellular targets. Physiologically based-pharmacokinetic/pharmacodynamic (PB-PK/PD) models are of great value for the design of active principles by the pharmaceutical industry and for the optimization and individualization of patient therapy. Experimental results from in vitro and in vivo studies can be used for building such models. On the other hand, properly designed models and simulation can contribute to a better design of experiments. Much of what is presented in this article applies equally well to drugs and other chemicals. Unless specified otherwise, reference to drugs applies also to other chemicals. This review is based on an expert meeting organized by COST Action B25 held in Eilat, Israel, on 14 – 15 February 2008. The authors have prepared this article to reflect the presentations and discussions at that meeting.

Keywords::

• active sites
• drug–drug interactions
• free (unbound) concentration
• PB-PK/PD models
• pharmaco/toxicodynamics
• pharmaco/toxicokinetics
• receptors
• signaling pathways
• systems biology
• targets
• transporters

Acknowledgements

This review is based on an expert meeting organized by COST Action B25 held in Eilat, Israel, on 14-15 February 2008. The authors have prepared this article to reflect the presentations and discussions at that meeting. Other members of the Management Committee of COST Action B25 are Leon Aarons (UK), Pavel Anzenbacher (Czech Republic), Melih Babaoglu (Turkey), Meir Bialer (Israel), Kim Brosen (Denmark), Jaroslav Chládek (Czech Republic), Hege Christensen (Norway), Nicolas Frey (Switzerland), Mats Karlsson (Sweden), Jochen Kuhlmann (Germany), Christian Laveille (France), Panos Macheras (Greece), Jussi Malkki (Finland), Jirina Martinkova (Czech Republic), Constantin Mircioiu (Romania), Gian Maria Pacifici (Italy), Jose Luis Pedraz Munoz (Spain), Alicia Rodriguez Gascon (Spain), Armel Stockis (Belgium), Achiel Van Peer (Belgium), and Umit Yasar (Turkey). Invited experts were Martin Göttlicher (Germany), Jukka Hakkola (Finland), Peter Moldeus (Sweden), Ronald Oude Elferink (Netherlands), Petr Pavek (Czech Republic), Shlomo Sasson (Israel), Johan Smit (Belgium), and Peter Webborn (UK).

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