BARRIERS TO DRUG DISTRIBUTION
The capillary membrane
between the plasma and brain cells is much less permeable to water-soluble
drugs than is the membrane between plasma and other tissues. Thus, the transfer
of drugs into the brain is regulated by the blood-brain
barrier. To gain access to the brain from the capillary circulation, drugs
must pass through cells rather than between them. Only drugs that have a high
lipid–water partition coefficient can penetrate the tightly apposed capillary
Drugs that are partially ionized
and only moderately lipid soluble will penetrate at considerably slower rates.
Lipid-insoluble or highly ionized drugs will fail to enter the brain in
significant amounts. Because the pH of the cerebrospinal fluid is about 7.35,
there is some tendency for weak organic bases to concentrate in the
cere-brospinal fluid and for weak organic acids to be ex-cluded. In addition,
because only the unbound form of a drug is available for diffusion, extensive
plasma pro-tein binding also can have dramatic effects on the ex-tent of drug
transfer into the brain.
Inflammation, such as occurs
in bacterial meningitis or encephalitis, may increase the permeability of the
blood-brain barrier, permitting the passage of ionized lipid-insoluble
compounds (e.g., penicillin and ampi-cillin) that would otherwise be restricted
from penetrat-ing into the brain extracellular fluid.
The flow of cerebrospinal
fluid is essentially unidirec-tional; that is, it flows from its site of
formation in the choroid plexus through the ventricles to its site of exit at
the arachnoid villi. Drugs in this fluid can either enter the brain tissue or
be returned to the venous circulation in the bulk flow of cerebrospinal fluid carried through the arachnoid
villi. Some drugs, such as penicillin, will not leave the cerebrospinal fluid
compartment by bulk flow but will be actively transported by the choroid plexus
out of the fluid and back into the blood. Finally, drugs may diffuse from brain
tissue directly into blood capillaries.
Though drugs appear to cross
the blood-brain bar-rier by passive diffusion, transporter systems in the
blood-brain barrier pump drugs back out
into the sys-temic circulation. As in the gut, the Pgp transporter sys-tem is
the primary active transporter in the blood-brain barrier identified to date.
This ATP-dependent trans-porter system picks up substrates that have crossed
the capillary endothelial cells and transports them back to the systemic
circulation, limiting their penetration into the CNS. Thus, not only are the
physicochemical prop-erties of the drug a determinant for penetration into the
CNS but penetration also depends on whether the drug is a substrate for the Pgp
An important consequence of
the existence of a va-riety of routes of drug removal from the brain is that
drugs that slowly penetrate the CNS may never achieve adequate therapeutic
brain concentrations. Penicillin, for example, is a less effective antibiotic
centrally than it is peripherally.
The blood vessels of the
fetus and mother are separated by a number of tissue layers that collectively
constitute the placental barrier.
Drugs that traverse this barrier will reach the fetal circulation. The
placental barrier, like the blood-brain barrier, does not prevent transport of all
drugs but is selective, and factors that regulate passage of drugs through any
membrane (e.g., pKa, lipid
solubility, protein binding) are applicable here.
In general, substances that
are lipid soluble cross the placenta with relative ease in accordance with
their lipid–water partition coefficient and degree of ioniza-tion. Highly polar
or ionized drugs do not cross the pla-centa readily. However, most drugs used
in labor and delivery are not highly ionized and will cross. They are generally
weak bases with pKa values
of about 8 and tend to be more ionized in the fetal bloodstream, since the pH
of fetal blood is around 7.3 as compared with the maternal blood pH of 7.44.
Differences in maternal and fetal blood pH can give rise to unequal
concentrations of ionizable drugs in the mother and the fetus.
Active efflux transporters
also exist in the placenta, analogous to the gut and blood-brain barrier. These
are Pgp, multidrug resistance–associated protein (MRP), and breast cancer
resistance protein (BCRP). These transport proteins are located in many tissues
but also appear to be expressed in the placenta. Though the sub-strate
specificities of these proteins have not been com-pletely described, they
appear to function as efflux transporters, moving endogenous and exogenous
chem-icals from the placental cells back to the systemic circu-lation. In this
way, they serve as a mechanism to protect the fetus from exposure to unintended
The existence of a barrier
between the blood and testes is indicated by the absence of staining in
testicular tissue after the intravascular injection of dyes. Morphological
studies indicate that the barrier lies beyond the capillary endothelial cells
and is most likely to be found at the specialized Sertoli–Sertoli cell
junction. It appears that Pgp, the efflux transporter protein, also plays a
role in forming this blood-testis barrier. This protein probably plays a role
in preventing certain chemotherapeutic agents from reaching specific areas of
the testis and thus hinders treatment of the neoplasm.