Drug Targeting Organ-Specific Strategies

28 2 Brain-Specific Drug Targeting Strategies
2.3.1 Physiological Transport Systems
2.3.1.1 Nutrient Carriers Versus Diffusion-mediated Uptake
As many of the essential nutrients of the brain (glucose, amino acids, nucleotides and others)
are highly hydrophilic and would not cross the BBB by diffusion in sufficient amounts, the
endothelial cells are endowed with membrane-bound specific transport proteins for the facilitated
uptake of these substances from the blood. Figure 2.2 gives examples of the brain
uptake of typical transport substrates in comparison to (drug-) compounds that depend on
passive diffusion-mediated uptake. Diffusional permeability is related to lipophilicity and
size or molecular weight for compounds below 400–600 Da [27].Transporters bind their substrate
molecules and change their conformation or temporarily open up a pore, allowing passage
across the plasma membrane. One of the transport proteins at the BBB is the hexose
transporter, GLUT1 [28]. It is a member of the Na + -independent family of glucose transporters
and is highly expressed at the BBB and at the B-CSF-B. The K M for glucose
(2–5 mM) coincides with the physiological range of blood glucose and is lower than that for
Figure 2.2. Specific transporters provide brain uptake of substrates or drugs, which exceeds the uptake
by lipid-mediated diffusion through the blood–brain barrier (BBB). This is obvious from the position of
these substrates 3–4 log orders above the regression line between lipophilicity (expressed as the log of
octanol–water partition coefficient, log P) and BBB permeability (expressed as log of the permeability
surface area product, log PS). The linear relationship between log PS and log P holds for substances with
molecular weights below 400–600 Da. Drugs falling 1–3 log orders below the regression line are
substrates of efflux mechanisms and/or have high molecular weights (given in parentheses). The
numbered compounds are a series of somatostatin analogues. AZT = azidothymidine. Reproduced with
permission from reference [121].