DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

126
SECTION I
GENERAL PRINCIPLES
orally administered, absorbed by the gut, and taken to the
liver, can be extensively metabolized. The liver is considered
the major “metabolic clearing house” for both
endogenous chemicals (e.g., cholesterol, steroid hormones,
fatty acids, and proteins) and xenobiotics. The
small intestine plays a crucial role in drug metabolism
since drugs that are orally administered are absorbed by
the gut and taken to the liver through the portal vein. The
xenobiotic-metabolizing enzymes located in the epithelial
cells of the GI tract are responsible for the initial
metabolic processing of most oral medications. This
should be considered the initial site of drug metabolism.
The absorbed drug then enters the portal circulation for its
first pass through the liver, where it can undergo significant
metabolism. While a portion of active drug escapes
metabolism in the GI tract and liver, subsequent passes
through the liver result in more metabolism of the parent
drug until the agent is eliminated. Thus, drugs that are
poorly metabolized remain in the body for longer periods
of time and their pharmacokinetic profiles show much
longer elimination half-lives than drugs that are rapidly
metabolized. Other organs that contain significant
xenobiotic-metabolizing enzymes include tissues of the
nasal mucosa and lung, which play important roles in the
metabolism of drugs that are administered through
aerosol sprays. These tissues are also the first line of contact
with hazardous chemicals that are airborne.
Within the cell, xenobiotic-metabolizing enzymes
are found in the intracellular membranes and in the
cytosol. The phase 1 CYPs, FMOs, and EHs, and some
phase 2 conjugating enzymes, notably the UGTs, are
all located in the endoplasmic reticulum of the cell
(Figure 6–2). The endoplasmic reticulum consists of
phospholipid bilayers, organized as tubes and sheets
throughout the cytoplasm, forming a network that has
an inner lumen that is physically distinct from the rest
of the cytosolic components of the cell and has connections
to the plasma membrane and nuclear envelope.
This membrane localization is ideally suited for the
metabolic function of these enzymes: hydrophobic molecules
enter the cell and become embedded in the lipid
bilayer, where they come into direct contact with the
Cell
Endoplasmic
reticulum
Nucleus
Mitochondria
Cytoplasm
Oxidoreductase-
CYP complex
Lumen
Endoplasmic reticulum
CYP-oxidoreductase
complex
CYP
ER
lipid
bilayer
Substrate
NADPH
S
Fe
O
e –
NADPH-CYP 450
oxidoreductase
Iron-protoporphyrin IX
(Heme)
M
P
N
M
P
N
Fe N
N
V
M
M
V
Figure 6–2. Location of CYPs in the cell. The figure shows increasingly microscopic levels of detail, sequentially expanding the areas
within the black boxes. CYPs are embedded in the phospholipid bilayer of the endoplasmic reticulum (ER). Most of the enzyme is located
on the cytosolic surface of the ER. A second enzyme, NADPH-cytochrome P 450
oxidoreductase, transfers electrons to the CYP where it
can, in the presence of O 2
, oxidize xenobiotic substrates, many of which are hydrophobic and dissolved in the ER. A single NADPH-CYP
oxidoreductase species transfers electrons to all CYP isoforms in the ER. Each CYP contains a molecule of iron-protoporphyrin IX that
functions to bind and activate O 2
. Substituents on the porphyrin ring are methyl (M), propionyl (P), and vinyl (V) groups.