Michael W. B. Bradbury

Hydrogen bonding part 46: a review of the correlation and prediction of transport properties by an lfer method: physicochemical properties, brain penetration and skin permeability†

A number of solute descriptors that relate to the ability of a solute to take part in solute-solvent interactions have been identified, quantified and incorporated into a multiple linear regression equation. This general solvation equation can then be used for the correlation and prediction of solute effects in transport processes, that is, processes in which the main step is either the equilibrium transfer, or the rate of transfer, of a solute from one phase to another. Examples discussed include the solubility of gases and vapours in water, various water-solvent partitions, blood-brain distribution, brain perfusion, and skin permeability.

Molecular factors influencing drug transfer across the blood-brain barrier

A recently reported approach to the prediction of blood‐brain drug distribution uses the general linear free energy equation to correlate equilibrium blood‐brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; π2H, solute dipolarity or polarizability; α2H and β2H, the hydrogen bond acidity or basicity, and VX, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood‐brain barrier in the rat.

Electrolytes and water in the brain and cerebrospinal fluid of the foetal sheep and guinea‐pig

1. Samples of cisternal cerebrospinal fluid (c.s.f.) and blood plasma have been obtained nearly simultaneously from foetal sheep of different ages, the foetus having been exteriorized and maintained in a normal state with respect to its blood gases and arterial pH. The brains were removed from these foetuses and also from foetal guinea‐pigs after exsanguination.

Compartments and barriers in the sciatic nerve of the rabbit

Near constant concentration of various radioactively labelled polar nonelectrolytes were maintained in the blood plasma of renal ligated rabbits. The uptake of [14C]urea, [51Cr]EDTA and [14C]inulin into sciatic nerve was interpreted in terms of a two-compartment model. There was a rapidly equilibrating space representing about 20% of the tissue weight which is almost certainly the interstitial fluid of the epineurium and outer layers of the perineurium. Urea penetrated the blood-nerve barrier at a similar rate to the entry of this compound into brain. Sucrose, chromium-EDTA and sulphate passed into the true interstitial fluid approaching a total volume of distribution of about 36% of the tissue weight at 6-8 h. Since movement of these 3 solutes is severely restricted by the blood-barrier, the blood-nerve barrier in the rabbit must contain channels of greater than 1 nm which are not present in the developed blood-brain barrier. Uptake of [3H]3-O-methylglucose into nerve was examined but the results did not give a conclusive answer to the question of whether there is specific transport of sugars at the blood-nerve barrier. The wet nerve contained (in mmole/kg) sodium 74.3; potassium 42.6 and chloride 48.8. Water was 64.6 ml/100 g. Intracellular electrolyte concentrations were estimated. Approximately 30% of the total sodium content cannot be accounted for as being free in the interstitial fluid at a Gibbs-Donnan distribution with plasma. Analysis of metabolically poisoned nerves which have equilibrated with salt solution in vitro suggests that negatively charged polyelectrolyte molecules retain about 14 mmole of sodium/kg wet normal nerve.

Uptake of 26-Al and 67-Ga into brain and other tissues of normal and hypotransferrinaemic mice

Aluminium uptake from blood into tissues of control and homozygous hypotransferrinaemic (hpx/hpx) mice, following continuous intravenous infusion of Al and Ga, has been compared with that of gallium, a proposed tracer for aluminium. Al uptake into tissues of control (hpx/+ and +/+) mice occurred in the order (expressed as a space): bone 464.7ml 100g; renal cortex 102.9ml 100g; liver 13.0ml 100g; spleen 8.4ml 100g and brain 0.8ml 100g. Ga uptakes were similar in liver, spleen and brain, but smaller in the renal cortex and bone, at one-third and one-fifth of the values for Al, respectively. In the hypotransferrinaemic mice, uptake of Ga into all tissues was increased, especially in renal cortex (ninefold) and bone (twentyfold) as compared with the controls. Increases in Ga uptakes into cerebral hemisphere, cerebellum and brain stem of the hypotransferrinaemic mice were 3.8, 4.2 and 2.8 fold, respectively. Al uptake into tissues of the hypotransferrinaemic mice was similar to control values except in bone where it was three times greater. Pre-treatment of control animals with the anti-transferrin receptor antibody, RI7 208, enhanced Ga uptake in all tissues, the effect being greatest in renal cortex (tenfold) and bone (ninefold). Ga uptakes into cerebral hemisphere, cerebellum and brain stem in the mice pre-treated with RI7 208 were 6.4, 6 and 10 times greater than in untreated mice, respectively. No influence of antibody on Al uptake into mouse tissues was observed except in spleen where it was three times greater than in untreated mice. Hence, transport of aluminium and gallium into mouse tissues is not similar under all conditions. Non-transferrin mediated transport of each metal can occur into all tissues, especially in renal cortex and bone, where gallium may be a suitable marker for aluminium.

Determination of aluminium in different tissues of the rat by atomic absorption spectrometry with electrothermal atomization

Atomic absorption spectrometry with electrothermal atomization was used for the determination of aluminium in brain, liver, spleen, kidney cortex, skeletal muscle and bone of the rat following digestion by nitric acid and in serum following simple dilution and in situ oxygen ashing. The method of standard additions in the presence of a chemical modifier, ammonium dihydrogen-phosphate, was essential for bone tissues. The detection limits ranged from 3 to 58 ng per gram of wet mass of tissue and were 4-19 times lower than the observed physiological levels of aluminium. The between-day precision for serum was 8.9% at a mean concentration of 6.8 micrograms I-1 and 2.4% at a mean concentration of 125.3 micrograms I-1. Additionally, repeated analyses of National Institute of Standards and Technology Standard Reference Material 1577b Bovine Liver gave a relative standard deviation of 12.2% (mean concentration = 0.8 microgram g-1). Of the tissues studied, bone had at least ten times higher levels of aluminium than others (0.959 +/- 0.322 micrograms g-1). The aluminium concentration in cerebellum (0.073 +/- 0.043 micrograms g-1) was approximately twice that in the cerebral hemisphere (0.034 +/- 0.009 micrograms g-1).

Contrasting uptakes of 59Fe into spleen, liver kidney and some other soft tissues in normal and hypotransferrinaemic mice : influence of an antibody against the transferrin receptor

Uptake of iron-59 from blood into various soft tissues of anaesthetized mice was investigated by continuous intravenous infusion of the radiotracer during 2 hr. The 59Fe was given either as ferrous chloride with ascorbate or as 59Fe-transferrin. Infusions were made into adult mice with and without pretreatment with a monoclonal antibody against transferrin receptors, and into hypotransferrinaemic mice and appropriate controls. In normal mice, 59Fe uptake into spleen was much higher than into other tissues and was 94-96% inhibited by the antibody. Inhibitions due to the antibody were less complete in liver and renal cortex, and there was evidence of some non-transferrin-mediated transport during infusion of 59Fe/ascorbate. In the hypotransferrinaemic mice, tissue uptakes of 59Fe during infusion of 59Fe/ascorbate were enormous, being two to three orders of magnitude greater than in the normal controls. The rank order for size of uptake was liver > renal cortex > pancreas > spleen > other tissues. All tissues examined have a considerable potential capacity for uptake of non-transferrin-bound iron, this being greatest in liver and renal cortex.

UPTAKE OF ALUMINUM AND GALLIUM INTO TISSUES OF THE RAT: INFLUENCE OF ANTIBODY AGAINST THE TRANSFERRIN RECEPTOR

Transport of aluminum and gallium from blood into rat tissues following continuous iv infusion of metals in different chemical forms has been investigated. Tissue uptake of aluminum and gallium was similar and highly dependent on the chemical species of the metals. Aluminum and gallium accumulated in liver and spleen when infused in the chloride form. Raised citrate markedly enhanced aluminum and gallium uptake into renal cortex and bone; in contrast with gallium-transferrin, citrate increased uptake of67Ga into renal cortex and bone by 8- and 14-fold respectively. Uptake of67Ga with citrate into renal cortex was around 3 times smaller than that of aluminum. The antitransferrin receptor antibody OX-26 enhanced67Ga uptake from gallium citrate into all rat tissues.67Ga from purified gallium-transferrin was also taken into all tissues in the presence of OX-26, the effect being greatest in renal cortex and bone. No influence of antibody on aluminum transport into rat tissues was, however, observed when aluminum was infused in the citrate form. Therefore, transport of aluminum and gallium into tissues is not similar under all conditions. Transport of each metal occurs into all tissues in the presence of antitransferrin receptor antibody. The potential for such transport is much greater in the case of gallium. Transport of aluminum and gallium citrate complexes appears important especially in the renal cortex and bone.

Hugh Davson--His Contribution to the Physiology of the Cerebrospinal Fluid and Blood–Brain Barrier

Since the early fifties, when he became interested in the fluids of the brain, Hugh Davson exerted an enormous influence on the field. It was rightly said of him by Tom Maren at a meeting in Bar Harbour in 1974, ‘‘Why, man, he doth bestride our narrow world like a Colossus.’’ No doubt, Hugh, with his great feeling for Shakespeare, appreciated the quotation. With somewhat erratic assistance from his father, he studied chemistry at University College London and graduated with First Class Honours in 1931. With support from the biochemist Jack Drummond, Hugh Davson and his contemporary Jim Danielli worked on the permeability barrier between the living cell and the outside world, using red blood cells. This led to the Davson–Danielli concept of the cell membrane, as a bimolecular film of lipid. The classic monograph describing this work, The Permeability of Natural Membranes (Davson and Danielli), was finally published in 1943. After working on the effects of nitrogen mustards on the eye and on the use of infrared technology to improve night vision during the war, he returned to London to help establish the Institute of Ophthalmology in Judd St. Here, he and his colleagues initiated studies on the fluids of the eye. Personal and intellectual differences with the director, Duke-Elder, finally led him to move back to University College, where the Medical Research Council supported him until his ‘‘retirement’’ in 1975. No doubt, an unwillingness to upstage his former colleagues at the Institute with primary research on the eye led him to concentrate on the fluids of the brain. Hugh Davson (1955) was the first to show unequivocally, by the use of a series of substituted thioureas, that lipid solubility is the main determinant of passive entry of compounds into cerebrospinal fluid (CSF) and brain from blood. He also made clear the close relation between CSF and the interstitial fluid of brain by measuring equal rates of 24Na uptake into each fluid. He confessed that he wrote The Physiology

Uptake of Ga-67 into rat cerebral hemisphere and cerebellum. Comparison with Fe-59.

Transferrin and transferrin receptors play an important role in the transport of iron into the brain. To determine whether gallium enters the brain by the same mechanism, uptakes of Ga and 59Fe have been compared under controlled conditions. Rates of gallium penetration into brain (K) were four times slower than those for 59Fe. Kin for Ga when infused with citrate were 0.88 ± 0.24 and 0.94 ± 0.39 x 10 ml gh for cerebral hemisphere and cerebellum, respectively. When infused as the transferrin complex, Ga uptake into the brain was not different from that when infused with citrate. The presence of the anti-transferrin receptor antibody OX-26 significantly reduced uptake of Fe by 60% and 64% into cerebral hemisphere and cerebellum, respectively. By contrast, pretreatment of rats with OX-26 enhanced the uptake of Ga into brain, particularly when infused with citrate; mean increases in uptake of Ga were 120% and 144% for cerebral hemisphere and cerebellum, respectively. Purified Ga-transferrin was also taken up into both brain regions examined in the presence of OX-26. These results indicate that the transport of non-transferrin bound gallium is an important mechanism for gallium uptake into brain.