A number of mechanisms in the central nervous system act together in parallel and affect the effective penetration of drugs into brain. These mechanisms will affect the measured brain distributions of a range of compounds and will result in actual brain uptakes lower than might be predicted from physico-chemical data. Strategies directed at increasing brain uptake of drugs that are substrates for specific efflux mechanisms need to be focused on designing reactivity with a transporter out of the drug molecule or by examining ways of inhibiting the activity of an efflux mechanism by coadministering a competitive or noncompetitive inhibitor of the efflux pump together with the desired drug. To be fully and successfully exploited, both strategies will require a greater knowledge of how these efflux mechanisms function and their precise locations within the CNS. A corollary of this line of reasoning is that combination therapies, in which two or more drugs in a mixture are substrates or inhibitors for an active efflux mechanism, may result in an unexpectedly high level of a potentially neurotoxic drug in the CNS as a result of interaction with these transporters.

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