Uptake, brain

Fuxe K, Andersson K, Nilsen OG, et al Toluene and telencephalic dopamine selective reduction of amine mrnover in discrete DA nerve terminal systems of the anterior caudate nucleus by low concentrations of toluene. Toxicol Lett 12 115—123,1982 Cause EM, Mendez V, Geller I Exploratory smdies of a rodent model for inhalant abuse. Neurobehav Toxicol Teratol 7 143—148, 1985 Gentry JR, Hill C, Malcolm R New anticonvulsants a review of applications for the management of substance abuse disorders. Ann Clin Psychiatry 14 233—245, 2002 Gerasimov MR, Ferrieri RA, Schiffer WK, et al Smdy of brain uptake and biodistribution of [llCjtoluene in non-human primates and mice. Life Sci 70 2811 — 2828, 2002... 

Abbott NJ (2006) In vitro models for examining and predicting brain uptake of drugs. In Taylor JB, Triggle DJ (eds) Comprehensive medicinal chemistry II. Elsevier, Oxford, Sect 5.13... 

Figure 7 Structure of an 18F-labeled pyrazole ligand for brain uptake (see Table...

Table 1 Brain Uptake Data for the 18F-labeled Pyrazole Ligand of Figure 7... 

The brain uptake properties of 99m Tc-complexes with the MRP-20 ligand make it and its derivatives potential candidates for rCBF imaging applications. MRP-20 forms a neutral-lipophilic complex with the 99mTcO+3 core by loss of three ionizable protons from the ligand backbone (Fig. 3) [16]. "mTc-MRP-20 and several of its analogues show high brain uptake and retention and exhibit regional cerebral deposition patterns that are related to rCBF [16], This complex is in clinical trials in Europe. 

Hydrophilic peptides and proteins are frequently large molecules they may enter the brain by carrier-mediated transport, receptor-mediated transcytosis, or by adsorptive-mediated transcytosis. Small peptides, such as di- and tripeptides are transported by the specific transporters, PepTl and PepT2, but neither of them is present at the BBB. Nevertheless, there is saturable brain uptake of the tripeptide glutathione and of several opioid peptides, suggesting that specific transporters, as... 

Zeneroli ML, Iuliano E, Racagni C, Baraldi M Metabolism of gamma-aminobutyric acid and brain uptake in galactosamine induced hepatic encephalopathy. J Neurochem 1982 33 1219-1222. 

Nehhg, A. Brain uptake and metabolism of ketone bodies in animal models. Prostaglandins Leukot. Essent. Fatty Acids 70 265-275, 2004. 

These refinements in our knowledge of brain penetration and CNS activity of drugs feature prominently in a major medicinal review of the blood-brain barrier [14]. In vivo perfusion studies on the rate of brain uptake of several non-steroidal anti-inflammatory drugs in rats with increasing concentration of albumin in the perfusate clearly demonstrate the effect of plasma protein binding on the rate (in addition to the extent at steady-state) of brain uptake [15]. 

Dagenais, C., Graff, C.L. and Pollack, G. M. (2004) Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochemical Pharmacology, 67, 269-276. 

Kandimalla KK, Donovan MD (2005) Transport of hydroxyzine and triprolidine across bovine olfactory mucosa role of passive diffusion in the direct nose-to-brain uptake of small molecules. Int J Pharm 302 133-144. 

The RUI method is a modification of the brain uptake index method [29] which was first described by Aim and Tornquist [4], The RUI approach consists of a single-arterial (e.g., intracarotid) injection technique, where the primary objective is to analyze the influx of the test substrate from the circulating blood to the retina through the BRB (i.e., blood-to-retina direction). This approach, for example, has been used to determine the retinal uptake of the test substrate which has a relatively high permeability across the BRB. The advantage of this approach is that it avoids the effect of plasma-protein binding of the test substrate and allows the retinal uptake of the test substrate... 

Burns and Weaver [6] developed an MLR-based BBB permeability model using two experimental measures of BBB penetrability (brain/plasma ratio and the brain-uptake index) and 14 theoretically derived biophysical predictors based on Stein s hydrogen-bonding number and Randic s topological properties of the molecules. The final model accurately predicted the ability of test molecules to cross the BBB. 

J. N. Jacob, V. E. Shashoua, A. Campbell, R. J. Baldessarini, y-Aminobutyric Acid Esters. 2. Synthesis, Brain Uptake, and Pharmacological Properties of Lipid Esters of y-Aminobutyric Acid , J. Med. Chem. 1985, 28, 106- 110. 

E. Shek, T. Murakami, C. Nath, E. Pop, N. S. Bodor, Improved Anticonvulsant Activity of Phenytoin by a Redox Brain Delivery System III Brain Uptake and Pharmacological Effects , J. Pharm. Sci. 1989, 78, 837-843. 

Techniques for Measurement of Brain Uptake 2.3.2.1 In vivo Methods... 

For the correct interpretation of brain uptake studies in general and for the pharmacokinetic validation of a given delivery strategy, it is necessary to be familiar with characteristics and limitations of the applied technique [41]. 7k vivo methods remain the gold standard, as there are still no cell culture models available that fully represent the barrier characteristics. 

Quantitative measurement of diffusional uptake and carrier-mediated transport of nutrients and drugs in experimental animals was greatly facilitated with the introduction of Olden dorfs brain uptake index (BUI) [42].Test and reference tracers are injected as an intraarterial bolus into the carotid artery of the anaesthetized animal. After 5 s the animal is killed and the brain is removed for radioactivity counting. This method measures the ratio of the unidirectional brain extraction, E, of the test substance and of the reference ([ H]-water, [ " C]-butanol), which are labelled with different isotopes, during a single passage through the brain capillary bed ... 

The most sensitive technique for measuring brain uptake is the intravenous bolus administration or infusion and subsequent measurement of brain concentrations (Figure 2.4). Depending on the pharmacokinetics of the test compound in plasma, brain sampling may be performed after suitable circulation times ranging from minutes to hours or days. 

The pharmacokinetic calculation of the unidirectional brain uptake rate, after intravenous injection, uses the relation of the brain concentration and the area under the curve of plasma concentration, AUC ... 

Here Cbrain is the brain concentration after correction for intravascular content, and AUC is determined between time 0 and the final sampling time. Two assumptions must hold when interpreting the evaluation in the simple form described above (1) the brain uptake of the compound is linear, meaning is dose independent, and (2) the analysis is performed within a time-frame where the efflux from tissue is negligible (tissue concentrations are sufficiently low compared to plasma concentrations). Violation of these assumptions requires adjustments in experimental design and evaluation. For example, nonlinear kinetics may be accounted for by incorporation of a MichaeUs-Menten term, while efflux can be treated by compartmental analysis [46]. 

The i.v. approach has the distinct advantage of measurements being carried out under the most physiological conditions. On the other hand, the caveats include confounding effects of peripheral metabolism, which may give rise to artifactual brain uptake of degradation products. To exclude such a possibility the application of suitable analytical techniques to tissue and plasma samples is required. 

An alternative delivery strategy for small molecules is based on the presence of the nutrient transporters. Drugs that are structurally similar to substrates of a carrier system can undergo facilitated brain uptake as pseudoneutrients. The best example of this is the therapeutic use of L-DOPA in Parkinson s disease. Unlike the neurotransmitter dopamine itself, which cannot cross the BBB in significant amounts, its precursor L-DOPA is a substrate for LAT, the transporter of large neutral amino acids [56]. Its uptake by the brain is saturable, and subject to competition by the other substrates of the carrier present in plasma. 

Brain uptake data for some vectors are compared in Table 2.1. Quantitative comparisons within the same species are possible for the rat with vectors derived from the anti-TfR monoclonal antibody 0X26 and from cationized human serum albumin. To put the efficiency of brain delivery into perspective, the comparison to a classical neuroactive drug may be informative. In the rat, brain concentrations of morphine following systemic administration never exceed 0.08% of injected dose per gram [%ID g ] [82]. In contrast, 0X26 easily reaches concentrations in rat brain that are three to four times higher. Vectors based on cationized hu-... 

The utility of [TcOCU] in Tc chemistry is demonstrated by the first synthesis of 8-hydroxy-quinoline (8-Hox, (126)) complexes of technetium in 1984. Ligand (126) is usually one of the first choices to explore the coordination chemistry of an element, but it was as late as 1984 when the first complex with Tc was prepared. It was known that the reaction of [ Tc04] with 8-Hox leads to complexes with high brain uptake, and it was therefore important to define the structure of the active species. This sequence of events is very typical for technetium chemistry. Nuclear medicinal experiments indentify a Tc species with useful biological behavior, which prompts investigations into the basic coordination chemistry to identify the structure of the Tc... 

Racemic mixtures of dadt ligands with substituents such as A -benzylpiperazinyl on the carbon backbone between the two nitrogen donors were reacted directly with [Tc04] in the presence of [8204], to yield mixtures of the corresponding syn and anti isomers. The syn form showed higher brain uptake and resided longer than the anti isomer, but with a phenylpiperi-dine substituent the syn and anti forms showed the reverse uptake/excretion behavior. ... 

---