BRAIN-BLOOD RATIO: IMPLICATIONS IN BRAIN DRUG DELIVERY

Drug Discovery, 2010

Drug disposition across the blood ‐brain barrier is frequently determined by measuring the distribution coefficient of drug between brain and plasma in vivo or by predicting the distribution coefficient from in vitro experiments. To render the distribution coefficient between brain and plasma (B/P ratio) a useful parameter for lead optimisation, it needs to be complemented with a measure of brain tissue binding, because it has been shown that only the free concentration of a drug in the brain relates to its pharmacodynamics. Methods for assessing drug disposition and brain tissue binding were reviewed and a new concept of brain availability has been introduced. Drug availability in the brain is defined as the product of the B/P ratio and the unbound fraction of drug in the brain. An easily accessible brain efficacy scale is introduced based on the proposed brain availability. Brain efficacy is defined as the ratio of brain availability over the drug’s inhibition constant. This relat...

Journal of Pharmacology and Experimental Therapeutics, 2007

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 interrelationship 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. 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 http://jpet.aspetjournals.org.

World Journal of Advanced Research and Reviews,, 2023

Abstract: Brain-targeted drug delivery is a field of research that seeks to develop new methods for delivering drugs to the brain. This is done by overcoming the blood-brain barrier (BBB), a network of cells that tightly regulate the flow of substances between the blood and the brain. Most of the time lipophilic drugs are easily cross blood brain barrier but few of them less soluble in lipid therefore they don’t cross the blood brain barrier. After review we concluded that we can easily improve the solubility of drug using various techniques and Brain-targeted drug delivery is a promising field of research that has the potential to revolutionize the treatment of brain diseases. With further advances, it is possible that brain- targeted drug delivery will become a standard treatment for a variety of brain diseases and disorders. Keywords: Blood Brain Barrier; Brain-Targeted; CNS; Lipophilic drug; Challenges

Many pharmaceuticals cannot access brain, though, has potential for treatment and this is mainly due to the potential blood brain barrier. To have a successful delivery, the challenges of anatomical and physiological aspects of those barriers need to be addressed. Though a considerable efforts were made in convincing those barriers, still designing a suitable delivery remains a major challenge. This review lists various strategies for the drug delivery to the brain. Sophisticated approaches like intracerebral delivery, intranasal delivery, barrier disruptions, receptor mediated transport, prodrugs, chemical drug delivery and many more were discussed. Limitations of some strategies were also discussed. Understanding the strategies along with the suitability of the therapeutic agent to undergo those strategic modifications would certainly promises the success of a brain drug delivery program. This a review made here would help the researcher in understanding the barrier and further modifying the therapeutic agent for the suitable drug or delivery.

The human brain represents the pinnacle of biological evolution. With grooves and spirals that give it the appearance of a shelled walnut, it weighs on average 1.3kg and contains 100 billion nerve cells (or neurons), with 10 times as many glial support cells. These cells are organised in a highly complex three-dimensional (3-D) array of interconnecting fibres, with information flow mediated by flux of electrical charge along communicating neuronal fibres (axons) at a speed of up to 250 miles/hour. This flow of information is mediated by the movement of charged ions across the axonal membrane; communication between neurons is via release of neurotransmitter into the synaptic space between adjacent cells. These communication points are numerous and in total the human brain contains 10 14 such synapses. Any given neuron may have several thousand synaptic connections to many other neurons, forming a highly complex network -the number of possible connections is virtually without limit. The activity of the brain weaves meaningful patterns to control all of our senses, actions, emotions and thoughts. Although constituting only 2% of the weight of the body, the brain Neurobiol, 2000;20:217-30. 8. Siegal T, Ruinstein R, Bokstein F, et al., In vivo assessment of the window of barrier opening after osmotic blood brain barrier disruption in humans, J Neurosurg, 2000;92:599-605. 9 Siegal T, Zylber-Katz E, Strategies for increasing drug delivery to the brain, Clin Pharmacokinet, 2002;41:171-86. 10. Kroll RA, Neuwelt EA, Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means, Neurosurgery, 1998;42:1083-1100.

Neurobiology of Disease, 2010

The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood-brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine. In vivo microdialysis provides a powerful method for the measurement of endogenous and exogenous substances in the ISF surrounding the probe and so it represents an important tool in CNS drug discovery. It can also be used to measure the pharmacodynamic response of neuroactive compounds by measuring neurotransmitters and second messengers. Another approach to measure both pharmacokinetics and the pharmacodynamics of neuroactive compounds is the measurement of receptor occupancy, which has the advantage of being applicable to the study of humans as well as experimental animals. Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds clearly improve understanding of the efficacy and safety of drug candidates, which improves both the efficiency and the effectiveness of CNS medicines research.

Revista de neurologia, 2010

To provide an updated view of the difficulties due to barriers and strategies used to allow the release of drugs in the central nervous system. The difficulty for the treatment of many diseases of the central nervous system, through the use of intra-venous drugs, is due to the presence of barriers that prevent the release of the same: the blood-brain barrier, blood-cerebro-spinal fluid barrier and the blood-arachnoid barrier. The blood-brain barrier is the main barrier for the transport of drugs in the brain that also acts as a immunologic and metabolic barrier. The endothelial cells of the blood-brain barrier are connected to a junction complex through the interaction of transmembrane proteins that protrude from de inside to the outside, forming a connection between the endothelial cells. The transport of substances to the brain depends on the mechanisms of transport present in the barrier and the diffusion of these compounds also depends on the physicochemical characteristics of t...

Journal of Drug Delivery and Therapeutics

A targeted drug delivery system is based on a technique that continuously administers a predetermined dosage of a therapeutic agent to a sick location of the body. The targeted drug delivery goal is to raise the relative amount of the treatment in the target tissues while lowering it in the non-target tissues. This technique's intrinsic benefit has been reduced drug dose and adverse effects. Drug targeting in the brain is one of the most challenging issues in pharmaceutical research because the blood-brain barrier acts as an impermeable barrier for systemically delivered therapeutics and the brain extracellular matrix contributes to the poor distribution of locally delivered drugs. In the treatment of various Central nervous system (CNS) diseases, general approaches that can improve drug delivery to the brain are of great interest. Drugs are less harmful and more effective when they are administered close to where they would be most effective. Extreme research studies have recen...