Blood-brain barrier, passage

D., Vander Heyden, Y. Classification tree models for the prediction of blood-brain barrier passage of drugs. /. Chem Inf. Model. 2006, 46, 1410-1419. 

Although in vitro GR 175737 is less potent (pKi = 8.2) than clobenpropit (pK = 9.8), in vivo GR 175737 shows a higher activity (ED3o 1.4 mg/kg) in an ex vivo binding assay than clobenpropit (ED50 = 10.3 mg/kg) [20], Apparently the bioavailability of GR 174737 is much better than clobenpropit and the authors postulated that this observed difference might be caused by the relative ease of blood-brain-barrier passage. 

Ayre SG, Skaletski B, Mosnaim AD (1989) Blood-brain barrier passage of azidodiymidine in rats Effect of insulin. Res Comm Chem Padi Pharmacol 63 45—52. 

Absorption Distribution Metabolism Excretion GI tract, lungs, skin Storage in tissues (plasma proteins, liver and kidney, fat, bone), blood-brain barrier, passage across the placenta, membrane permeability Liver, lungs, kidney, brain, phase I, phase II metabolism Urinary, fecal, exhalation, milk, sweat, sahva... 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

FIGURE 29-1. The blood-brain barrier selectively inhibits certain substances from entering the interstitial spaces of the brain and spinal fluid. It is thought that certain cells within the brain form tight junctions that prevent or slow the passage of certain substances. Levodopa passes the blood-brain barrier, whereas dopamine is unable to pass. 

Oxazepam is available in oral form only, so it is useful only for uncomplicated withdrawal. Other benzodiazepines are available in injectable form and will be further described below. Diazepam and lorazepam are more lipophilic than chlordiazepoxide and oxazepam, resulting in quicker gastrointestinal absorption and passage across the blood-brain barrier, which makes them valuable in an inpatient setting, especially to treat or prevent seizures. However, their faster onset of action maybe associated with feeling high, which can be a disadvantage of their use. 

The blood-brain barrier forms the interface between the bloodstream and the brain parenchyma and thus controls the passage of endogenous substances and xenobiotics into and out of the central nervous system. Brain microvessels exhibit a variety of unique structural features, such as an extremely tight endothelium without fenestration, a very low rate of pinocytosis, tight junctions between endothelial cells excluding paracellular permeability, and a series of polarized transport proteins. The following chapter describes the structural and functional characteristics of the blood-brain barrier with emphasis on transport proteins, as well as in vitro techniques, which allow studying this complex barrier in the brain. 

Transferrin Passage through the blood-brain barrier uptake in tumour cells and other proliferating cells... 

An ability to penetrate lipid bilayers is a prerequisite for the absorption of drugs, their entry into cells or cellular organelles, and passage across the blood-brain barrier. Due to their amphiphilic nature, phospholipids form bilayers possessing a hydrophilic surface and a hydrophobic interior (p. 20). Substances may traverse this membrane in three different ways. 

Uses The endogenous opioids (metenkephalin, leuenkephalin, p-en-dorphin) cannot be used therapeutically because, due to their peptide nature, they are either rapidly degraded or excluded from passage through the blood-brain barrier, thus preventing access to their sites of action even after parenteral administration (A). 

Data on distribution give an indication of whether a particular tissue may be exposed to the substance or not. The extent of chemical distribution into tissues depends on the extent of plasma protein and tissue binding and this may vary among species. This is also the case for passage of chemicals into the brain, which is protected by the blood-brain barrier. 

Between the free CSF space and the extracellular space there is a diffusion equilibrium for macromolecules. The intra/extracellular barrier and the blood-brain barrier are essentially lipid barriers, retaining small hydrophilic molecules but allowing the passage of lipophilic molecules up to approximately 500 Da... 

Entacapone is a reversible inhibitor of peripheral catechol-O-methyltransferase (COMT). It is given at the dose of 200 mg with each dose of levodopa. It prolongs the action of levodopa and reduces synthesis of 3-O-methyldopa which is presumed to antagonize dopa passage through the blood-brain barrier. 

Inflammation, such as occurs in bacterial meningitis or encephalitis, may increase the permeability of the blood-brain barrier, permitting the passage of ionized... 

AU of the following statements concerning the blood-brain barrier and the passage of drugs from the systemic circulation into the cerebrospinal fluid are TRUE EXCEPT ... 

Not all substances in the bloodstream can readily gain entry into the brain. This apparent barrier to drugs and other chemicals is relative rather than absolute, and in fact there are several barriers to substances entering the brain from the systemic circulation. The term blood-brain barrier is usually applied to the lack of passage of certain drugs or other exogenously administered chemicals into the brain. 

A. The site of the blood-brain barrier was hotly debated for many years until electron micrographs clearly showed that endothelial cells lining brain capillaries are so closely joined to each other that passages of substances cannot readily occur through the intercellular clefts located between adjacent cells and that this constitutes a barrier to the passage of many substances from the blood to the parenchyma of the brain. 

Lithium is readily absorbed from the gastrointestinal tract, reaching a peak plasma level in 2 to 4 hours. Distribution occurs throughout the extracellular fluid with no evidence of protein binding. Passage through the blood-brain barrier is limited, so that cerebrospinal fluid levels are 50% of plasma levels at steady state. 

Figure 11.1 The blood-brain barrier prevents the passage of large molecules, such as proteins, into the brain. Small molecules, such as glucose and molecules found in drugs of abuse, are able to pass through the barrier.

While the specific mechanisms of action of interferon-pia and interferon-pib in MS are not fully understood, each interferon has a number of immune-mediating activities (see Section 7.1). A recent review article on multiple sclerosis observed The interferons reduce the proliferation of T cells and the production of tumor necrosis factor a, decrease antigen presentation, alter cytokine production to favor ones governed by type 2 helper T (Th2) cells, increase the secretion of interleukin-10, and reduce the passage of immune cells across the blood-brain barrier by means of their effects on adhesion molecules, chemokines, and proteases [2]. 

Two obstacles effectively prohibit this availability. Serotonin has a free hydroxy group (the 5-hydroxy which is the H of 5-HT). This is a big polar water-loving pimple which denies it any passage across the brain s defensive Maginot Line, the blood-brain barrier. And there is the second problem. There is a exposed amino group, the amine of T of 5-HT, the tryptamine, which is immediately removed by the body s monoamine oxidase enzyme. In short, it is blocked from entry into the brain because it is both too polar and too metabolically fragile. 

Consequently, many foreign compounds achieve the same concentration in fetal as in maternal plasma. However, if metabolism in utero converts the compound into a more polar metabolite, accumulation may occur in the fetus. Despite extensive blood flow (16% cardiac output 0.5 mLmin 1g 1 of tissue), entry of foreign compounds into the brain takes place much less readily than passage into other tissues. Hence, the term "blood-brain barrier." Ionized compounds will not penetrate the brain in appreciable quantities unless they are carried by active transport systems. The reasons for this are as follows ... 

After passage through the blood brain barrier, opioids have an anti-emetic effect (Blancquaert et al., 1986). Emesis inhibition is induced via blockade of an emesis centre located in a more central area of the formatio reticularis. This explains why the emetic effect of opioids is most apparent immediately after anministration, especially after rapid intravenous administration and is reduced or terminated when the compound has reached the CNS. The more hydrophilic opioids like morphine have stronger emetic side-effects than lipophilic compounds like methadone or fentanyl (Barnes et al., 1991), which are rapidly transported into the CNS. 

---