Assays to predict drug permeation across the blood-brain barrier, and distribution to brain.

Drug discovery programmes to target or avoid the brain need to take into account the properties of the blood-brain barrier (BBB). The importance to CNS PK of the free drug concentration in brain is increasingly recognised, and assays for drug discovery programmes are being adjusted accordingly. In vitro models of the BBB continue to play an important role in this process. Good cell-based models using brain endothelium have been developed and validated for mechanistic studies, and some are suitable for medium to high throughput permeability screening and toxicology. Brain homogenate and brain slice methods allow estimation of drug partition into brain. In combination with in silico and in vivo models, the portfolio of methods establishing and predicting CNS drug PK is now very powerful, allowing much more accurate iterative feedback to chemists to optimise compound profiles through the drug discovery and development programme. The advantage of using models based on real BBB cellular anatomy and physiology is that they have the power to reveal and incorporate previously undiscovered properties, such as new transporters, metabolic enzymes and modulation, to form the basis for models mimicking neurological disorders as well as normal function, and to allow physiologically-based pharmacokinetic (PBPK) extrapolation from animal models to humans.

The blood-brain barrier in systemic lupus erythematosus.

Central nervous system (CNS) involvement may occur in 20-70% of systemic lupus erythematosus (SLE) patients where neurological symptoms are overt; this is termed neuropsychiatric lupus or NPSLE. This review summarizes evidence that damage to the brain endothelium forming the blood-brain barrier (BBB) is a contributory factor in NPSLE. The normal CNS is protected by blood-tissue barriers at three sites, the brain endothelium (BBB), the choroid plexus epithelium (blood-CSF barrier) and the arachnoid epithelium. The tight junctions of the barrier layers severely restrict entry of plasma constituents including proteins, so that the CSF and brain interstitial fluid contain low levels of protein. Methods for diagnosing BBB damage include imaging (CT, MRI) using contrast agents, and analysing protein content and profiles of CSF Changes in the albumin quotient Qalbumin show evidence for barrier damage, while changes in the immunoglobulin (Ig) index can indicate intrathecal antibody production. However, BBB damage may be transient, and hence undetected or underestimated. Few mechanistic studies exist, but the two main candidate mechanisms for BBB damage are microthrombi in cerebral vessels leading to ischaemia, and immune-mediated attack and activation of the endothelium leading to local cytokine production. Both can result in barrier breakdown. Neurological syndromes could then be secondary to damage to the BBB. The implications for treatment of NPSLE are discussed.

Lithium transport by the colon of normal and sodium-depleted rats.

1. The transport of Li by colonic epithelium has been examined in normal and Na-depleted rats. 2. Substitution of Li for Na with lumen of the conon causes the transepithelial electrical potential difference (p.d.) and short-circuit current to fall to low levels and the electrical resistance of fall moderately. Recovery occurs by fairly slowly after removal of Li. 3. Li absorption increases linearly with increasing concentration in the lumen and is significantly faster in Na-depleted rats. Increasing the luminal Na concentration reduces Li absorption from solutions of low Li concentration. 4. Comparison of absorption rates with secretion rates in rats given Li systemically, together with measurements of Li distribution across the epithelium in relationship to the transepithelial p.d. indicate that Li transport is predominatly or entirely passive. Interference with Li absorption by Na suggests, however a mucosal membrane carrier which, since Li absorption rises after Na depletion, may be increased in the Na-depleted state.

The effect of lithium on the transport of sodium, potassium and chloride by the colon of normal and sodium-depleted rats.

1. The effect of Li, given systemically or placed in the gut lumen, on the transport of Na, K and C1 and on the transepithelial electrical potential difference (p.d.) was studied in vivo in the distal colon of normal and Na-depleted rats. 2. The specific effect of Li appeared to be on the Na transport system with K and C1 transport affected only indirectly. Active Na absorption was impaired and p.d. reduced when either Li was in the lumen or given systemically. In addition with Li in the lumen, a considerable rise in the plasma-to-lumen Na flux was observed, the flux increasing progressively with rising intraluminal Li concentration. The effects were greater in Na-depleted rats. 3. The greater part of Li absorption from the colon of the rat takes place by exchange for Na, the secretion of which is much enhanced while the p.d. is reduced. This contrasts with human colon in which potassium is the ion exchanged for Li with the p.d. increased.