PHARMACOKINETICS AND BIOPHARMACEUTICS (46:138)
LECTURE TUTORIAL
Passage of
Xenobiotics Across Biological Membranes
Key Terms:
Biotransport: The translocation of a
solute from one side of a biological barrier to the other side in the intact
form. When used to speak of crossing an external membrane (such as the skin or
gastrointestinal tract), we usually use the term absorption. But this is
still a biotransport process.
Passive diffusion: The movement of drug across
a membrane in a manner driven solely by the concentration gradient. In passive
diffusion, drug moves from a region of greater concentration to a region of
lesser concentration.
Carrier-mediated diffusion: Movement of drug across a
cell membrane via a specialized transport system embedded in the cell membrane.
When this occurs without the consumption of energy, it is referred to as facilitated
diffusion. This manner of biotransport does not move drug against a
concentration gradient. On the other hand, active transport
requires energy and can move drug against a concentration gradient (i.e., from
a region of lesser concentration to a region of greater concentration).
Permeability: The ease with which a
solute penetrates a membrane. It is determined by the physicochemical
properties of the solute and the biophysical characteristics of the membrane.
The net rate of penetration of a solute is a function of the permeability, the
concentration gradient, and the surface area to which the solute is exposed.
Paracellular diffusion: The movement of drug across
a membrane by going between, rather than through, two cells. By definition,
this process is solely passive and is dependent upon pore size, as well as the
size and shape of the xenobiotic.
Transcellular diffusion: The movement of a drug
across the cell. When intestinal absorption occurs by transcellular diffusion,
the drug is exposed to the enzymes within the cell, as well as any efflux pumps
that are present on the apical region of the membrane. These may result in a
reduction in the amount of drug that reaches the systemic circulation.
Transcellular diffusion may be passive, facilitated, or active.
Key Principles:
Surface area is the most
important determinant of biotransport across the gastrointestinal tract: While many factors influence
the absorption of drugs across the gastrointestinal tract, the surface area is
the most important factor. For example, based on pH-pKa
considerations, one would anticipate that salicylate would be most extensively
absorbed in the stomach. As a weak acid, it will be mostly unionized in the
acidic environment of the stomach, which should favor its absorption. In the
small intestine, where the pH is ~6, the drug will be largely ionized and,
therefore, in an environment unfavorable for absorption. In reality, however,
salicylate is absorbed much more extensively from the small intestine than from
the stomach. This is because the surface area of the small intestine is several
orders of magnitude greater than the stomach. This increased surface area of
the small intestine ‘overcomes’ the negative effect of the greater ionization
of the drug in the intestinal environment.
Mechanisms of biotransport can be differentiated by examining the effect
of increasing concentrations: The two primary mechanisms of biotransport, passive
diffusion and carrier-mediated transport, differ in their behavior as drug
concentration increases. In carrier-mediated transport, drug must bind with a
carrier protein in order to cross the cell membrane. There are a limited number
of these proteins on any given cell surface, so there is a finite capacity for
transport of drug across the membrane. Thus, carrier-mediated transport is a
saturable process, whereas passive diffusion is not. As a consequence, when the
dose of a compound that is absorbed by passive diffusion is increased, the
percent of the dose that is absorbed remains the same. In contrast, there is a
decrease in the percent of the dose that is absorbed when increasing the dose
of a drug absorbed by a carrier-mediated process.
Biotransport is not a
one-way process: You’ve heard the saying, “What goes up, must come down”? Well, in like
manner, “What goes in a cell, must come back out.” At least, that is usually
the case. But how does it come out? Sometimes the rate of removal of drug from
inside the cell is far more efficient than the rate of entry into the cell. If
you think about it, this is a very good protective mechanism for cells. It can
prevent toxic compounds from accumulating intracellularly. That is precisely
the reason some tumor cells are resistant to anticancer drugs – drugs that
undergo biotransport into the cell are removed so efficiently that the
concentration of the antitumor drug never gets high enough to kill the tumor
cell. Studies identified a specific transport protein referred to as multidrug
resistance protein that is responsible for this removal of drugs from
cells. It is now known that there are numerous cellular proteins capable of preventing
intracellular accumulation of drugs by pumping drug that enters the cell right
back out. These are sometimes called efflux pumps. One of the
most important is p-glycoprotein, which is present in many
different tissues in the body (e.g., intestine, placental membrane, blood-brain
barrier). P-glycoprotein is responsible for the poor bioavailability and low
CNS concentrations of numerous drugs. Indeed, one hot area of research in the
pharmaceutical industry is to identify compounds that are potent inhibitors of
P-glycoprotein and other efflux pump proteins. Such inhibitors can enhance the
effectiveness of some antitumor drugs.
Practice Problems:
1.
When
drug concentration on both sides of a membrane become equal, diffusion of drug
across the membrane ceases if the drug undergoes passive diffusion. True or
False? Answer
2.
Draw
a graph showing the relationship of net rate of penetration across a membrane
versus Kp for a drug structure with a molecular weight ~250 g/mole. Answer
3.
As a non-ionizable compound, ethanol is not
influenced by the low pH of the stomach and is, therefore, primarily absorbed
from this region of the gastrointestinal tract. True or False? Answer
4.
A
recent study in mice demonstrated that the pro-inflammatory cytokine
interleukin-6 is able to down-regulate (decrease) the expression of p-glycoprotein. Interleukin-6 is released in
response to a wide variety of inflammatory stimuli. If this effect also occurs
in humans, one would expect the oral bioavailability of drugs that are
substrates for p-glycoprotein to be:
a)
increased b) decreased c) unchanged
in the presence of
interleukin-6. Answer
Last revised 06/04/04
ă 2004 - Craig K. Svensson, Pharm.D., Ph.D.
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