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Chapter: Modern Pharmacology with Clinical Applications: Drug Absorption and Distribution

Physiological 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.


Blood-Brain Barrier

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 endothelial cells.

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 transporter system

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.

Placental Barrier

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 chemicals.

Blood-Testis Barrier

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.

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