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Mechanisms of transport across the gastrointestinal membrane There are two main mechanisms of drug transport across the gastrointestinal epithelium: transcellular (i.e. Therefore the rate of appearance of drug in the blood at the absorption site is given by d d C t = − k where dC/dt is the rate of appearance of drug in the blood at the site of absorption, k is the proportionality constant, Cg is the concentration of drug in solution in the gastrointestinal fluid at the absorption site and Cb is the concentration of drug in the blood at the site of absorption. The proportionality constant k incorporates the diffusion coefficient of the drug in the gastrointestinal membrane (D), and the thickness (h) and surface area of the membrane (A): k A h = D

Thus the small
intestine, primarily the duodenum, is the major site
of drug absorption, owing principally to the presence
of villi and microvilli, which provide such a large
surface area for absorption (discussed earlier in this
chapter). These equations indicate that the rate of gastro-
intestinal absorption of a drug by passive diffusion
depends on the surface area of the membrane that
is available for drug absorption. 19.1 also indicates that the rate of drug absorp-
tion depends on a large concentration gradient of
drug existing across the gastrointestinal membrane.

Membrane transport can be divided into active
transport and facilitated transport. The gastrointestinal absorption of a weak electrolyte drug is enhance when the pH at the site of absorption favours the
formation of a large fraction of the drug in aqueous
solution that is un-ionized. These
uptake transporters use a variety of porter mechanisms
(i.e.

Symporters (or cotransporters) transport ions and substrates simultaneously in the same direction, while
antiporters (or counter transporters) simultaneously
transport ions in one direction and substrates in the
opposite direction. Uncompetitive
binding occurs when the inhibitor binds to the
intermediate of the substrate–transporter complex
to terminate the translocation step. Noncompetitive inhibition occurs when the inhibitor
binds not to the transporter active site but to an
allosteric site, which lowers the affinity of the
transporter for the substrate due to changing the
conformation of the transporter.

Many peptide-like drugs, such as the penicillins,
cephalosporins, angiotensin-converting enzyme (ACE)
inhibitors and renin inhibitors, rely on the peptide
transporters for their efficient absorption. Nucleosides
and their analogues for antiviral and anticancer drugs
depend on the nucleoside transporters for their
uptake. Competition between two similar substances for
the same transfer mechanism and the inhibition of
absorption of one or both compounds and temperature
dependence are characteristics of carrier-mediated transport.

Inhibition of absorption may also be
observed with agents that interfere with cell metabo-
lism. Transcytosis
Transcytosis is a mechanism for transcellular transport
in which a cell encloses extracellular material via an
invagination of the cell membrane to form a vesicle
(endocytosis), then moves the vesicle across the cell
to eject the material through the opposite cell
membrane by the reverse process (exocytosis). Specific membrane transport-
ers are expressed in the luminal and/or basolateral
membranes of enterocytes, hepatocytes, renal tubular epithelial cells and other important barrier tissues,
including the blood–brain barrier, blood–testis barrier
and the placental barrier.

proteins or particles, are absorbed; it is not an
important route for oral absorption of drugs that are
in solution. Transcytosis is also a means by which some viruses,
bacteria and prion proteins can gain entry to the
lymphatic system through absorption by enterocytes
and specialized cells (M cells) in the gut-associated
lymphoid tissue (GALT). Endocytosis can be further subdivided
into four main processes: clathrin-mediated endocy-
tosis, macropinocytosis, caveolin-mediated endocytosis
and phagocytosis.

Paracellular pathway
The paracellular pathway differs from all the other
absorption pathways as it is the transport of materials
in the aqueous pores between the cells rather than
across them. The paracellular pathway can be divided into
convective (‘solvent drag’) and diffusive components. Drugs absorbed
by the paracellular route include the H2-antagonist
cimetidine, the antidiarrheal loperamide, the β-blocker
atenolol and the bisphosphonate tiludronate.

In summary, drugs can be absorbed via passive
diffusion, via membrane transporters or carrier-
mediated pathways, paracellular transport or trans-
cytosis. A drug can cross the intestinal epithelium
via one pathway or a combination of pathways. For example, the major
cytochrome P450 enzyme CYP3A, present in the
liver and responsible for the hepatic metabolism of
many drugs, is present in the intestinal mucosa, and
intestinal metabolism may be important for substrates
of this enzyme.

Hepatic metabolism
The liver is the primary site of drug metabolism and
thus acts as a final barrier for oral absorption.The bioavailability of
sustained-release propranolol is even less as the drug
is presented via the hepatic portal vein more slowly
than from an immediate-release dosage form, and
the liver is therefore capable of extracting and
metabolizing a larger portion.The bioavailability of a susceptible drug may be
reduced to such an extent as to render the gastro-
intestinal route of administration ineffective, or to necessitate an oral dose which is many times larger
than the intravenous dose (e.g. propranolol).