Role of the blood-brain barrier in disposition of endobiotics and xenobiotics

Abstract

Event Abstract Back to Event Role of the blood-brain barrier in disposition of endobiotics and xenobiotics Olavi Pelkonen1* 1 University of Oulu , Department of Pharmacology and Toxicology, Finland The pharmacokinetic (PK) behaviour of drugs is determined principally by metabolism (drugmetabolizing enzymes) and transport (uptake and efflux transporters). The role of phase I and II enzymes is quite established, but the role of transporters is less well delineated, although it is quite clear that they are often crucial for drug disposition. The third important factor is the regulation of the enzymes and transporters by, for example, ligand-activated nuclear receptors in the organs of importance for PK. Most attention to these players has been paid in the case of organs determining systemic PK, i.e. liver, gastrointestinal tract, lungs and kidneys. It is worth of remembering that the flow of endobiotics and xenobiotics through other internal organs and barriers is also profoundly controlled by the three above mentioned players - enzymes, transporters and regulatory factors - which ensure by a coordinated action that the organ gets necessary, even vital, endobiotics and discards lipophilic xenobiotics, which otherwise could cause disturbances in the internal milieu. On the other hand, it may be prudent to stress that xenobiotics, being "foreign to the body", may not be handled in the same strict manner as endobiotics and thus can cause disturbances in the homeostasis of cells, organs and the whole body, which may be either beneficial (desired drug actions) or detrimental (harmful effects of chemicals). One of the topics which COST Action B25 has been trying to develop is 'local kinetics and dynamics', i.e. behaviour and actions of substances in cells, tissues and organs. One of the most important goals of this work has been to elucidate important local determinants affecting disposition of chemicals in a given cell or tissue and how ensuing changes in local concentrations of a chemical are reflected in therapeutic or toxicological responses. Some basic approaches and concepts of this work have been published in recent review articles by COST B25 members (Pelkonen et al 2008; Kapitulnik et al 2009). One of the examples has been brain tissue and blood-brain barrier (BBB). Access to brain tissue and ensuing effects of substances are dependent on their ability to cross the BBB. The BBB is a physical and functional barrier that controls the entrance of many drugs and chemicals into brain cells regardless of their molecular size. The BBB and adjacent brain cells at the level of functionally important molecules, at the level of tissue architecture, and at the level of kinetic modeling, are illustrated in the attached figure 6 from Pelkonen et al (2008). From the local kinetics point of view it is of importance to catalogue and elucidate the determinants of the movement and disposition of substances across the BBB. Determinants affecting concentration at the BBB - Systemic pharmacokinetics (ADME), plasma protein binding, local blood flow (a limiting factor for drugs that can easily pass the BBB). Determinants affecting movement across the membrane Determinants affecting movement across the membrane - Passive diffusion (physicochemical characteristics of the drug such as hydrophilicity, lipophilicity, hydrogen bonding, etc). - Active transport and metabolism (efflux and influx transporters, such as P-gp and MRPs, membrane drug metabolising enzymes). Determinants affecting extracellular and intracellular brain concentration - Binding to brain tissue components. - Cell-specific transporters. - Cell-specific drug metabolizing enzymes (e.g. CYP2D6). It is clear that the elucidation of the above mentioned determinants for the BBB and for specific brain areas is by no means a mean task. However, it is necessary to elucidate at least the role of rate-limiting determinants, because they are most important for the building of reliable and valid models of BBB and brain tissue. pic 3 pic 2 pic 1