Tools To Study Cns Drug Delivery

Penetration of the BBB is essential for effective pharmacotherapy of CNS disorders. Various techniques have been used to study the pharmacokinetics and pharmacodynamics of CNS active agents by determining unbound drug concentrations in the extracellular fluid of the brain. In vivo techniques include the brain uptake index (27), the brain efflux index (BEI) (28), brain perfusion (29), the unit impulse response method (30) and micro-dialysis (31).

BEI, an intracerebral microinjection technique, can be used to examine BBB efflux transport mechanisms under in vivo conditions. The BEI method may be employed to determine the apparent in vivo drug efflux rate constant across the BBB and to monitor drug concentration dependency and efflux inhibition (32).

CSF concentrations are commonly used as a surrogate marker of CNS availability of drugs. The equilibrated CSF-to-unbound plasma concentration ratio may be a good indicator of the balance between drug permeability across the blood-CNS barriers and the sink action of CSF turnover. As lipophilicity and membrane permeability increase, the CSF-to-plasma unbound concentration ratio increases toward unity. Deviations are noted for lipophilic drugs that are highly bound to CSF proteins (ratios >1), and lipophilic drugs that are efflux transporter substrates (ratios <1). Despite the complexity of CSF pharmacokinetics, a rapid kinetic equilibrium exists between the CSF and biophase for certain medications. In these cases, drug concentration in the CSF can serve as a proximate reference for detailed investigations of factors affecting the intrinsic pharmacodynamics of a centrally acting drug (33). For the direct measurement of the brain interstitial fluid drug concentration, a determinant of the in vivo effect of a drug in the CNS, brain microdialysis can be a useful tool (34-36). However, intracerebral microdialysis is an invasive technique, which may cause tissue trauma and therefore affect BBB function.

In order to study CNS drug transport more efficiently, some in vitro models that closely mimic the in vivo system have been developed to predict the BBB permeability of drugs. Three types of brain capillary endothelial cell culture, including primary cultures, cell lines and co-culture systems, are currently used as in vitro BBB models (37). Generally, the in vitro BBB model consists of a co-culture of brain capillary endothelial cells on one side of a filter and astrocytes on the other, and a good in vivo and in vitro correlation has been demonstrated for the investigation of the role of the BBB in the delivery of nutrients and drugs to the CNS (38,39). Other BBB models have been developed from cerebral capillary endothelium (porcine brain capillary endothelial cells) or choroid plexus epithelial cells (porcine choroid plexus) (40,41).

The permeability of the BBB is just one of the factors determining the drug bioavailability in the brain. The BBB generally only allows passage of select lipophilic drugs by passive diffusion. As mentioned previously, the transmembrane protein P-gp is one of the carrier systems that transport drugs out of the brain through efflux. P-gp affects the pharmacokinetics of many drugs, and can be inhibited by administration of modulators or competitive substrates. Therefore, identification and classification of CNS drugs as P-gp substrates or inhibitors are of crucial importance in drug development.

Similar to CNS drugs, delivery of diagnostic agents also presents several challenges as a result of the special features of CNS blood vessels and tissue fluids. The anatomy of large vessels can be imaged using bolus injection of X-ray contrast agents to identify sites of malformation or occlusion, and blood flow can be measured using magnetic resonance imaging (MRI) and computed tomography (CT), while new techniques permit analysis of capillary perfusion and blood volume. Absolute quantities can be derived, although relative measures in different CNS regions may be as useful in diagnosis.

Local blood flow, blood volume, and their ratio (mean transit time) can be measured with high speed tomographic imaging using MRI and CT. Intravascular contrast agents for MRI are based on high magnetic susceptibility and include gadolinium, dysprosium and iron. Recent advances in MRI technology permit non-invasive "labeling" of endogenous water protons in flowing blood, with subsequent detection as a measure of blood flow. Imaging the BBB most commonly involves detecting disruptions of the barrier, allowing contrast agents to leak out of the vascular system.

Techniques for imaging the dynamic activity of the brain parenchyma mainly involve Positron Emission Tomography (PET), using a variety of radiopharmaceuticals to image glucose transport and metabolism, neuro-transmitter binding and uptake, protein synthesis and DNA dynamics. PET studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, and this may result in improved drug therapy (42). In addition, PET can be used for assessment of mechanisms underlying drug resistance in epilepsy, examination of the role of the BBB in the pathophysiology of neurodegenerative and affective disorders, and exploration of the relationship between polymorphisms of transporter genes and the pharmacokinetics of test compounds within the CNS (43). PET methods also permit detailed analysis of regional function by comparing resting and task-related images, which is important in improving understanding of both normal and pathological brain function (44).

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