Brain concentration

Gupta PK, Gupta RC. 1977b. Influences of endosulfan on pentobarbitone sleeping time and blood and brain concentrations in male rats. J Pharm Pharmacol 29 245-246. 

Since these studies utilized autoradiographic techniques, it was important to determine the chemical nature of the material measured using radiochemical procedures. Using punch biopsies of the brain slices which were measured autoradiographically, it was shown using thin-layer chromatography that about 30% of the radioactivity was associated with unchanged BCNU (14). It was therefore concluded that the measurements described above accurately reflect brain concentrations of BCNU. 

Acetylcholine is synthesised in nerve terminals from its precursor choline, which is not formed in the CNS but transported there in free form in the blood. It is found in many foods such as egg yolk, liver and vegetables although it is also produced in the liver and its brain concentration rises after meals. Choline is taken up into the cytoplasm by a high-affinity (Am = 1-5 pM), saturable, uptake which is Na+ and ATP dependent and while it does not appear to occur during the depolarisation produced by high concentrations of potassium it is increased by neuronal activity and is specific to cholinergic nerves. A separate low-affinity uptake, or diffusion (Am = 50 pM), which is linearly related to choline concentration and not saturable, is of less interest since it is not specific to cholinergic neurons. 

ACh is widely distributed throughout the brain and parts of the spinal cord (ventral horn and dorsal columns). Whole brain concentrations of lOnmolg" tissue have been reported with highest concentrations in the interpeduncular, caudate and dorsal raphe nuclei. Turnover figures of 0.15-2.0 nmol g min vary with the area studied and the method of measurement, e.g. synthesis of labelled ACh from [ " C]-choline uptake or rundown of ACh after inhibition of choline uptake by hemicholinium. They are all sufficiently high, however, to suggest that in the absence of synthesis depletion could occur within minutes. 

The main problem with any study of prostaglandins (PGs) is that although brain concentrations can exceed 0.1 /rg/g, they appear to be formed on demand, rather than preformed and stored and they have very short half-lives (seconds). Also specific effective antagonists remain to be developed and PGs are widely and evenly distributed, unlike many NTs. Thus any analysis of their central effects rests heavily on either studying PG release, or their effects when applied directly (icv injection). Certainly the brain has the enzymatic ability to synthesise both prostaglandins (cycloxygenase) and leukotrienes (lypoxygenase) from arachidonic acid (AA) (see Fig. 13.8) and a number of central functions have been proposed for them (see Piomelli 1994). 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Serotonergic neurons contain the enzyme L-tryptophan-5-monooxygenase (EC 1.14.16.4), more commonly termed tryptophan hydroxylase, which converts tryptophan to 5-hydroxytryptophan (5-HTP) (Fig. 13-5). Tryptophan hydroxylase contains 444 amino acids, corresponding to a molecular weight of about 51 Da. This enzyme is synthesized in serotonergic cell bodies of the raphe nuclei and is found only in cells that synthesize 5-HT. Therefore its distribution in brain is similar to that of 5-HT itself. The Km of tryptophan hydroxylase for tryptophan is approximately 30-60 pmol/1, a concentration comparable to that of tryptophan in brain. If the concentration of tryptophan in serotonergic neurons is assumed to be comparable to that in whole brain, the enzyme would not be saturated with substrate, and the formation of 5-HT in brain would be expected to rise as the brain concentration of tryptophan increases. This has been found to occur in response to raising the dietary intake of tryptophan specifically. 

Peak brain concentrations occur 12 to 60 minutes after IV dosing. On average, seizures are controlled within minutes of the loading dose. 

Bufotenine has been found to be behaviorally inactive, or only weakly active, in most animal studies, although at 15 mg/kg, it did produce the head-twitch resonse in mice (43). It was also behaviorally active in experiments in which the blood-brain barrier was bypassed (78). Acylation of the polar hydroxy group of bufotenine increases its lipid solubility (65,74) and apparently enhances its ability to cross the blood-brain barrier (64). For example, O-acetylbufotenine (5-acetoxy-N,N-dimethyltryptamine 54) disrupted conditioned avoidance behavior in rodents (65) and produced tremorigenic activity similar to that elicited by DMT (37) or 5-OMeDMT (59) when administered to mice (64). In this latter study, a comparison of brain levels of bufotenine after administration of O-acetylbufotenine with those of DMT and 5-OMeDMT revealed bufotenine to be the most active of the three agents, based on brain concentration. The pivaloyl ester of bufotenine also appears to possess behavioral activity, since stimulus generalization was observed when this agent was administered to animals trained to discriminate 5-OMeDMT from saline (74). 

A recent report on a NR2B selective NMDA receptor antagonist (9) supports the findings of Kalvass and Maurer [56], Rapid equilibration between plasma and CNS coupled with the lack of Pgp substrate activity led the authors to assume that plasma-free and brain-free drug concentrations were equivalent. An ex vivo receptor binding assay showed 50% occupancy at a total plasma concentration of 230 nM. Given a rat-free fraction of 15.3%, the authors concluded that 50% brain occupancy occurred at 35 nM unbound brain concentration, which was in reasonable agreement with the measured Ki of 3.4 nM versus the human receptor. 

Chen PH, Tilson HA, Marbury GD, et al. 1985. Effect of chlordecone (Kepone) on the rat brain concentrations of 3-methoxy-4-hydroxyphenylglycol Evidence for a possible involvement of the norepinephrine system in chlordecone-induced tremor. Toxicol Appl Phannaeol 77 158-164. 

It is difficult to draw firm conclusions about the relevance of this central action of 3-blockers in animals to their clinical anti-hypertensive activity bearing in mind that brain concentrations of the different drugs varies widely... 

Brain delivery of steroid hormones is also of interest to medicinal chemists. Again, most data available on CDSs of steroids pertain to rates of oxidation of the dihydropyridine carrier, to blood and brain concentrations, and to pharmacological activities. The latter can then be taken as proof of efficient cerebral hydrolysis of the pyridinium metabolite. Thus, the dihydrotrigonelline carrier allowed good brain delivery of estradiol and some other estrogens [181][182],... 

D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, l-Dopa Esters as Potential Prodrugs Behavioural Activity in Experimental Models of Parkinson s Disease , J. Pharm. Pharmacol. 1987, 39, 627 - 635 D. R. Cooper, C. Marrel, H. van de Waterbeemd, B. Testa, P. Jenner, C. D. Marsden, L-Dopa Esters as Potential Prodrugs Effect on Brain Concentration of Dopamine Metabolites in Reserpi-nized Mice , J. Pharm. Pharmacol. 1987, 39, 809-818. 

Kornhuber J, Quack G, Danysz W, Jellinger K, Danieiczyk W, Gsell W, Riederer P. (1995). Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Neuropharmacology. 34(7) 713-21. 

Nashelsky et al. (1995) described one non-fatal assault and three deaths in which chloroform was utilized. Blood and/or tissue concentrations of chloroform were determined in the assault victim and one decedent within 24 hours, within 10 days in another decedent who was frozen for the majority of that period, and after 5 months without preservation in the last decedent. Blood concentrations in 2 decedents were 2 and 3 pg/mL fat concentrations were 10 and 42 pg/mL brain concentrations were 3 and 46 pg/mL and the liver concentration in one decedent was 24 pg/mL. Due to the nature of the tissues analyzed, these data should be regarded as qualitative indicators of chloroform absorption only. 

Functional interactions between the nicotinic and cannabinoid systems have been proposed (Cohen et al. 2002) and several studies have tested the applicability of these ideas to nicotine discrimination. However cannabinoid agonists acting at cannabinoid CBi and CB2 receptors have failed to generalise with nicotine (Zaniewska et al. 2006). Results with the anandamide uptake and fatty acid amide hydrolase inhibitors AM-404 and URB 597, that elevate brain concentrations of endogenous cannabinoids, were also negative. Furthermore, neither the CBi receptor... 

Free tryptophan is transported into the brain and nerve terminal by an active transport system which it shares with tyrosine and a number of other essential amino acids. On entering the nerve terminal, tryptophan is hydroxylated by tryptophan hydroxylase, which is the rate-limiting step in the synthesis of 5-HT. Tryptophan hydroxylase is not bound in the nerve terminal and optimal activity of the enzyme is only achieved in the presence of molecular oxygen and a pteridine cofactor. Unlike tyrosine hydroxylase, tryptophan hydroxylase is not usually saturated by its substrate. This implies that if the brain concentration rises then the rate of 5-HT synthesis will also increase. Conversely, the rate of 5-HT synthesis will decrease following the administration of experimental drugs such as para-chlorophenylalanine, a synthetic amino acid which irreversibly inhibits the enzyme. Para-chloramphetamine also inhibits the activity of this enzyme, but this experimental drug also increases 5-HT release and delays its reuptake thereby leading to the appearance of the so-called "serotonin syndrome", which in animals is associated with abnormal movements, body posture and temperature. 

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