BBB permeability is always a question for researchers looking for the CNS acting drugs. Basically, in-vitro tools are used to access the efficacy of the test compounds, even though results are positive BBB permeability is always a question.
This is the big caveat we currently have with in vitro BBB models (and even with in vivo models too). The major drawback of current models are the difference in barrier tightness measured by transendothelial electrical resistance (TEER) between in vitro (
What is the evidence that drugs always enter the brain via the blood vessels? What about the lymphatic system? Some at least of the CSF drains directly into the lymphatic system, and many organisms are able to access the CSF via this route. For instance, children can have bacteria in the blood without these causing problems, whereas they can sometimes creep up from the respiratory tract and lymph nodes into the brain, causing meningitis.
Looking at the process of drug delivery and reaching out to each and every organ and part of the body, tell us how important it is for a drug to be present in blood. Regarding BBB, most of the drugs to treat CNS disorders are either given orally or in inject able forms.
Oral drugs are absorbed by lymphatics in the stomach and distributed to the rest of the body via the lymphatic vascular system.
The reason CNS drugs are not given nasally, for example, is due to lack of imagination, not of evidence (see Nasal Administration on Wikipedia). Where this has been tried, with intranasal oxytocin for example, this has been successful. The drug has evidently spread rapidly up pre-lymphatic pathways into the CSF/brain.
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