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Modeling bioavailability to organs protected by biological barriers.

Quignot N - In Silico Pharmacol (2013)

Bottom Line: On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction.In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models.Data from such assays are very useful to calibrate PBPK models.

View Article: PubMed Central - PubMed

Affiliation: Bioengineering Department, Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Royallieu Research Center, Compiègne, 60200 France ; LA-SER, Strategy and Decision Analytics, 10 place de la Catalogne, Paris, 75014 France.

ABSTRACT
Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.

No MeSH data available.


Related in: MedlinePlus

Dynamics at the level of physiological barriers. Epithelial and endothelial cell layers may form selectively permeable barriers, by which molecules pass either between the cells (paracellular route), or through the cells (transcellular route). The paracellular route is restricted by tight junction complexes, composed of communicating junctions, adherens junctions, and tight junctions. Influx mechanisms include carrier-mediated influx, receptor transcytosis, and absorptive-mediated transcytosis. The most known carrier efflux mechanism is mediated by P-glycoprotein.
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Fig1: Dynamics at the level of physiological barriers. Epithelial and endothelial cell layers may form selectively permeable barriers, by which molecules pass either between the cells (paracellular route), or through the cells (transcellular route). The paracellular route is restricted by tight junction complexes, composed of communicating junctions, adherens junctions, and tight junctions. Influx mechanisms include carrier-mediated influx, receptor transcytosis, and absorptive-mediated transcytosis. The most known carrier efflux mechanism is mediated by P-glycoprotein.

Mentions: The key role of blood-tissue barriers is to modulate and restrain permeability (Alexis et al. 2008). They are both physical and biochemical. Physical barriers consist in a layer of cells with closely associated membranes between adjacent cells. Membrane occlusion is mediated by protein complexes, like occludins and claudins for the tight junctions, cadherins for adherens junctions, and connexins for gap junctions. Biochemical barriers involve the metabolism of chemicals by metabolizing enzymes like cytochromes P450, the influx or efflux of chemicals by carrier protein like ATP-Binding cassette transporters such as P-glycoprotein (P-gp). A complex and dynamic multi-pathways process is involved in passage of molecules across biological compartments (Figure 1).Figure 1


Modeling bioavailability to organs protected by biological barriers.

Quignot N - In Silico Pharmacol (2013)

Dynamics at the level of physiological barriers. Epithelial and endothelial cell layers may form selectively permeable barriers, by which molecules pass either between the cells (paracellular route), or through the cells (transcellular route). The paracellular route is restricted by tight junction complexes, composed of communicating junctions, adherens junctions, and tight junctions. Influx mechanisms include carrier-mediated influx, receptor transcytosis, and absorptive-mediated transcytosis. The most known carrier efflux mechanism is mediated by P-glycoprotein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230447&req=5

Fig1: Dynamics at the level of physiological barriers. Epithelial and endothelial cell layers may form selectively permeable barriers, by which molecules pass either between the cells (paracellular route), or through the cells (transcellular route). The paracellular route is restricted by tight junction complexes, composed of communicating junctions, adherens junctions, and tight junctions. Influx mechanisms include carrier-mediated influx, receptor transcytosis, and absorptive-mediated transcytosis. The most known carrier efflux mechanism is mediated by P-glycoprotein.
Mentions: The key role of blood-tissue barriers is to modulate and restrain permeability (Alexis et al. 2008). They are both physical and biochemical. Physical barriers consist in a layer of cells with closely associated membranes between adjacent cells. Membrane occlusion is mediated by protein complexes, like occludins and claudins for the tight junctions, cadherins for adherens junctions, and connexins for gap junctions. Biochemical barriers involve the metabolism of chemicals by metabolizing enzymes like cytochromes P450, the influx or efflux of chemicals by carrier protein like ATP-Binding cassette transporters such as P-glycoprotein (P-gp). A complex and dynamic multi-pathways process is involved in passage of molecules across biological compartments (Figure 1).Figure 1

Bottom Line: On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction.In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models.Data from such assays are very useful to calibrate PBPK models.

View Article: PubMed Central - PubMed

Affiliation: Bioengineering Department, Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Royallieu Research Center, Compiègne, 60200 France ; LA-SER, Strategy and Decision Analytics, 10 place de la Catalogne, Paris, 75014 France.

ABSTRACT
Computational pharmacokinetic (PK) modeling gives access to drug concentration vs. time profiles in target organs and allows better interpretation of clinical observations of therapeutic or toxic effects. Physiologically-based PK (PBPK) models in particular, based on mechanistic descriptions of the body anatomy and physiology, may also help to extrapolate in vitro or animal data to human. Once in the systemic circulation, a chemical has access to the microvasculature of every organ or tissue. However, its penetration in the brain, retina, thymus, spinal cord, testis, placenta,… may be limited or even fully prevented by dynamic physiological blood-tissue barriers. Those barriers are both physical (involving tight junctions between adjacent cells) and biochemical (involving metabolizing enzymes and transporters). On those cases, correct mechanistic characterization of the passage (or not) of molecules through the barrier can be crucial for improved PBPK modeling and prediction. In parallel, attempts to understand and quantitatively characterize the processes involved in drug penetration of physiological barriers have led to the development of several in vitro experimental models. Data from such assays are very useful to calibrate PBPK models. We review here those in vitro and computational models, highlighting the challenges and perspectives for in vitro and computational models to better assess drug availability to target tissues.

No MeSH data available.


Related in: MedlinePlus