Drug modification, blood-brain barrier

Juillerat-Jeaimeret, L., 2008. The targeted delivery of cancer drugs across the blood-brain barrier chemical modifications of drugs or drug-nanoparticles Drug Discovery Today 13 (23-24), 1099-1106. 

One possibility to enhance, in a controlled manner, entry of drugs into the CNS would be to alter P-glycoprotein function at the blood-brain barrier. Such an enhancement could result from (1) direct modification of export pump function by inhibitors and intracellular signals or (2) bypassing the export pump by delivery systems not being recognized as substrates (e.g., nanoparticles or vector-coupled liposomes, which are taken up by endocytotic mechanisms) [58-65],... 

Membrane permeability is one of the most important determinants of pharmacokinetics, not only for oral absorption, but also for renal re-absorption, biliary excretion, skin permeation, distribution to a specific organ and so on. In addition, modification of membrane permeability by formulation is rarely successful. Therefore, membrane permeability should be optimized during the structure optimization process in drug discovery. In this chapter, we give an overview of the physiology and chemistry of the membranes, in vitro permeability models and in silica predictions. This chapter focuses on progress in recent years in intestinal and blood-brain barrier (BBB) membrane permeation. There are a number of useful reviews summarizing earlier work [1-5]. 

Di et al. [69] describe the use of a PAMPA for the prediction of passage of a drug across the blood-brain barrier by the modification of the membrane using porcine polar brain lipid and have demonstrated the ability to determine which compounds will be most likely to be CNS positive and CNS negative. 

Grieg, N. H. (1989). Drug Delivery to the Brain by Blood-Brain Barrier Circumvention and Drug Modification. In E. A. Neuwelt (Ed.), Implications of the Blood-Brain Barrier and Its Manipulation. New York Plenum Medical Book Co. 

Kroll, R. A., Pagel, M. A., Muldoon, L. L., et al. Improving drug delivery to intracerebral tumor and surrounding brain in a rodent model A comparison of osmotic versus bradykinin modification of the blood-brain and/or blood-tumor barriers. Neurosurgery 43(4) 879-886 discussion 886-879. 1998. 

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