Parenteral Delivery of Peptides and Proteins - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 533

tribution, rapid clearance, extensive degradation, or protein binding can reduce the
blood concentration of the peptide and thus result in low availability to the CNS.
A major challenge in this regard, however, is the delivery of P/P drugs over the
BBB. The BBB represents a complex system of mechanisms that act together to reg-
ulate the exchange of fluids and substances between the CNS and blood, as depicted
in Fig. 11.1 .
The barrier consists of an endothelial or capillary barrier and the ependymal bar-
rier found at the circumventricular organs and choroid plexus. Circumferential “tight
junctions” exist between the cerebral capillary endothelial cells, which do not allow
paracellular transport and are responsible for the production of a high electrical

Lumen of blood vessel

Astrocyte

Pericyte

Basement membrane

Endothelial cell

Neuron Tight junction

a
Paracellular aqueous
pathway

c
Transport proteins

e
Adsorptive
transcytosis

b
Transcellular
lipophilic
pathway
Lipophilic
substance

d
Receptor-mediated
transcytosis
Insulin,
transferrin,
LDL, leptin

Efflux

Glucose,
nucleosides,
amino acids,
vincristine

Plasma proteins
Ex. Albumin

Water-soluble
agents

Blood

Tight
junction

P-gp, MRP1, MRP2, MRP4,
MRP5, Datp2, Datp3,
BCRP are involve in cell
influx/eflux mechanism,
inhibited by verapamil
(P-gp, MRP1),
zosuquidar(P-gp)

Endothelium

Brain

Astrocyte

Astrocyte

Figure 11.1 Schematic diagram of brain anatomy and mechanisms that act together to regulate
the exchange of fluids and substances between the CNS and blood.