Novel models for assessing blood-brain barrier drug permeation.
Humans; Animals; Blood-Brain Barrier/*metabolism; *Capillary Permeability; Drosophila melanogaster/metabolism; Grasshoppers/metabolism; High-Throughput Screening Assays; Pharmaceutical Preparations/*metabolism; Zebrafish/metabolism; Models; Animal
INTRODUCTION: The blood-brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. AREAS COVERED: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). EXPERT OPINION: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.
Geldenhuys Werner J; Allen David D; Bloomquist Jeffrey R
Expert opinion on drug metabolism & toxicology
2012
2012-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17425255.2012.677433" target="_blank" rel="noreferrer noopener">10.1517/17425255.2012.677433</a>
Hepatocyte nuclear factor 4alpha regulation of bile acid and drug metabolism.
Humans; Animals; Gene Expression Regulation; Lipid Metabolism; Liver/metabolism; Signal Transduction/physiology; Bile Acids and Salts/*metabolism; Genetic Predisposition to Disease; Mutation; Pharmaceutical Preparations/*metabolism; Hepatocyte Nuclear Factor 4/genetics/*metabolism
The hepatocyte nuclear factor 4alpha (HNF4alpha) is a liver-enriched nuclear receptor that plays a critical role in early morphogenesis, fetal liver development, liver differentiation and metabolism. Human HNF4alpha gene mutations cause maturity on-set diabetes of the young type 1, an autosomal dominant non-insulin-dependent diabetes mellitus. HNF4alpha is an orphan nuclear receptor because of which the endogenous ligand has not been firmly identified. The trans-activating activity of HNF4alpha is enhanced by interacting with co-activators and inhibited by corepressors. Recent studies have revealed that HNF4alpha plays a central role in regulation of bile acid metabolism in the liver. Bile acids are required for biliary excretion of cholesterol and metabolites, and intestinal absorption of fat, nutrients, drug and xenobiotics for transport and distribution to liver and other tissues. Bile acids are signaling molecules that activate nuclear receptors to control lipids and drug metabolism in the liver and intestine. Therefore, HNF4alpha plays a central role in coordinated regulation of bile acid and xenobiotics metabolism. Drugs that specifically activate HNF4alpha could be developed for treating metabolic diseases such as diabetes, dyslipidemia and cholestasis, as well as drug metabolism and detoxification.
Chiang John Y L
Expert opinion on drug metabolism & toxicology
2009
2009-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1517/17425250802707342" target="_blank" rel="noreferrer noopener">10.1517/17425250802707342</a>