The blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) form a very effective barrier to the free diffusion of many polar solutes into the brain. Many metabolites that are polar have their brain entry facilitated by specific inwardly-directed transport mechanisms. In general the more lipid soluble a molecule or drug is, the more readily it will tend to partition into brain tissue. However, a very significant number of lipid soluble molecules, among them many useful therapeutic drugs have lower brain permeability than would be predicted from a determination of their lipid solubility. These molecules are substrates for the ABC efflux transporters which are present in the BBB and BCSB and the activity of these transporters very efficiently removes the drug from the CNS, thus limiting brain uptake. P-glycoprotein (Pgp) was the first of these ABC transporters to be described, followed by the multidrug resistance-associated proteins (MRP) and more recently breast cancer resistance protein (BCRP). All are expressed in the BBB and BCSFB and combine to reduce the brain penetration of many drugs. This phenomenon of "multidrug resistance" is a major hurdle when it comes to the delivery of therapeutics to the brain, not to mention the problem of cancer chemotherapy in general. Therefore, the development of strategies for bypassing the influence of these ABC transporters and for the design of effective drugs that are not substrates and the development of inhibitors for the ABC transporters becomes a high imperative for the pharmaceutical industry.
The dispositions of 50 marketed central nervous system (CNS) drugs into the brain have been examined in terms of their rat in situ (P) and in vitro apparent membrane permeability (P app ) alongside lipophilicity and free fraction in rat brain tissue. The inter-relationship between these parameters highlights that both permeability and brain tissue binding influence the uptake of drugs into the CNS. Hydrophilic compounds characterized by low brain tissue binding display a strong correlation (R 2 ϭ 0.82) between P and P app , whereas the uptake of more lipophilic compounds seems to be influenced by both P app and brain free fraction. A nonlinear relationship is observed between logP oct and P over the 6 orders of magnitude range in lipophilicity studied. These findings corroborate recent reports in the literature that brain penetration is a function of both rate and extent of drug uptake into the CNS.The development of new drugs targeting the central nervous system (CNS) is the fastest growing franchise within the pharmaceutical sector, although this growth has been tempered by relatively poor success of novel candidates (Alavijeh et al., 2005). One of the significant challenges in treating CNS conditions is drug passage across the blood-brain barrier (BBB), a layer of endothelial cells connected with tight junctions that express numerous drug-metabolizing enzymes and efflux transporters (Pardridge, 1997;Tamai and Tsuji, 2000). Therefore, investigation of drug properties that are favorable for CNS delivery can greatly improve efforts in drug discovery.A number of methods are available to determine the rate of uptake of drugs from blood into brain parenchyma (Begley, 1999). In the pharmaceutical industry, CNS penetration is usually assessed in rodents following either intravenous or oral dosing to determine the brain-to-blood concentration ratio. This takes into account not only BBB penetration but also binding, metabolism, and clearance. However, there can be marked species differences in the influence of these parameters on overall BBB penetration; hence, there is significant value in removing some of this complexity and assessing brain penetration at the level of the BBB in situ. Considering that the BBB is conserved across species (Cserr and Bundgaard, 1984), this may represent a more meaningful indicator of the intrinsic ability of the compound to cross the BBB in humans. Furthermore, in situ techniques offer an ideal validation tool for assessing in vitro BBB models, and they also provide further insight into the molecular descriptors that are crucial for BBB penetration.Brain perfusion has been used in neurochemical research for more than 50 years. Early methods focused on long-term perfusion of isolated brain and required extensive surgical Article, publication date, and citation information can be found at
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