The ins and outs of antiviral drug transport in the brain.

The ins and outs of antiviral drug transport in the brain The study of drug transport in brain has held a unique status, due, in large part, to the specialized barriers (i.e. blood brain barrier, BBB; blood:cer-ebrospinal ¯uid barrier, CSF:interstitial ¯uid barrier) that isolate the brain from the rest of the body. These barriers, for the most part, restrict drug access under normal physiological conditions, and in so doing, lead to bleak consequences for central nervous system (CNS) disease. Pursuant to the realization that drug uptake into brain may be minimal, a swell of methodologies have attempted to quantitate and improve upon these de®ciencies. Antiviral and antiretroviral drugs, particularly nucleoside and antisense oligonucleotides, are susceptible to the transport limitations in brain, that has propelled active ®elds of research on drug design, and delivery. In this issue of the Journal of NeuroVirology, Groothuis and Levy (1997) provide a timely and noteworthy assessment of the state of research on the CNS transport of antiviral drugs. An introductory section succinctly reviews the anatomy and physiology of the brain as it pertains to drug transport, and some of the associated methods of analysis. A key point made by the authors is that brain extracellular ¯uid (ECF) and cerebrospinal ¯uid (CSF) drug concentrations should not be assumed equal, due to the distinct, yet heterogeneous , pia-ependyma barrier, as well as due to the diffusional distances a drug must traverse once inside the ECF compartment. As exempli®ed both through models and experimental data, brain parenchyma drug concentrations are likely to decrease tremendously, and as a function of distance from the pia-ependyma barrier following local drug administration into the CSF. Two methodological points pertaining to measured brain concentrations warrant comment. First, the authors emphasize the importance of acknowledging the compartmental nature of brain (i.e. vascular, extracellular and intracellular components) and thus, correcting total brain drug concentrations for the vascular contribution is essential. This epitomizes the normal lumping of compartments, integral to methodologically-limited tissue homogenate studies, to attain singular concentration values. Even though the nature of vascular corrections are variable, and species-dependent, it is warranted, particularly for drugs with low BBB diffusivities. Brain microdialysis provides a means to obtain compartment-speci®c drug concentrations by insertion of a probe into brain extracellular ¯uid. This method has been applied to a host of drugs in animals with normal brain, and more recently in animals with brain-tumors (Devineni et al, 1996). The …