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

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SECTION I
GENERAL PRINCIPLES
constitute phase 1 oxidation and phase 2 conjugation.
As a general paradigm, metabolism serves to convert
these hydrophobic chemicals into more hydrophilic
derivatives that can easily be eliminated from the body
through the urine or the bile.
In order to be accessible to cells and reach their
sites of action, drugs generally must possess physical
properties that allow them to move down a concentration
gradient into the cell. Many drugs are hydrophobic,
a property that allows entry through the lipid bilayers
into cells where the agents can interact with their target
receptors or proteins. With some compounds, entry into
cells is facilitated by a large number of transporters on
the plasma membrane (see Chapter 5). This property of
hydrophobicity renders drugs difficult to eliminate,
since in the absence of metabolism, they accumulate in
fat and cellular phospholipid bilayers in cells. The
xenobiotic-metabolizing enzymes serve to convert
drugs and other xenobiotics into derivatives that are
more hydrophilic and thus easily eliminated through
excretion into the aqueous compartments of the tissues.
The process of drug metabolism that leads to elimination
also plays a major role in diminishing the biological
activity of a drug. For example, (S)-phenytoin, an
anticonvulsant used in the treatment of epilepsy, is virtually
insoluble in water. Metabolism by the phase 1
cytochromes P450 (CYPs) followed by phase 2 uridine
diphosphate-glucuronosyltransferases (UGTs) produces
a metabolite that is highly water soluble and readily eliminated
from the body (Figure 6–1). Metabolism also terminates
the biological activity of the drug. Since conjugates
are generally hydrophobic, elimination via the bile
and/or urine is dependent on the actions of many efflux
transporters (see Chapter 5).
While xenobiotic-metabolizing enzymes are responsible for
facilitating the elimination of chemicals from the body, paradoxically
these same enzymes can also convert certain chemicals to highly
reactive, toxic, and carcinogenic metabolites. This occurs when an
unstable intermediate is formed that has reactivity toward other
cellular constituents. Chemicals that can be converted by xenobiotic
metabolism to cancer-causing derivatives are called carcinogens.
Depending on the structure of the chemical substrate, xenobioticmetabolizing
enzymes can produce electrophilic metabolites that
react with nucleophilic cellular macromolecules such as DNA, RNA,
and protein. This can cause cell death and organ toxicity. Reaction
of these electrophiles with DNA can sometimes result in cancer
through the mutation of genes, such as oncogenes or tumor suppressor
genes. It is generally believed that most human cancers are due
to exposure to chemical carcinogens. This potential for carcinogenic
activity makes testing the safety of drug candidates of vital importance.
Testing for potential cancer-causing activity is particularly
critical for drugs that will be used for the treatment of chronic
Phenytoin
4-Hydroxyphenytoin
4-Hydroxyphenytoinglucuronide
HO
CYP
UGT + UDP-GA
Highly lipophilic
Slightly soluble
in water
Very soluble in
water
NH
O
COOH
O O
OH
HO
OH
Figure 6–1. Metabolism of phenytoin by phase 1 cytochrome P450
(CYP) and phase 2 uridine diphosphate-glucuronosyltransferase
(UGT). CYP facilitates 4-hydroxylation of phenytoin. The hydroxy
group serves as a substrate for UGT that conjugates a molecule of
glucuronic acid (in green) using UDP-glucuronic acid (UDP-GA) as
a cofactor. This converts a very hydrophobic molecule to a larger
hydrophilic derivative that is eliminated via the bile.
diseases. Since each species has evolved a unique combination of
xenobiotic-metabolizing enzymes, non-primate rodent models cannot
be the only animal models used for testing the safety of new drug
candidates targeted for human diseases. Nevertheless, testing in
rodent models, such as mice and rats, can usually identify potential
carcinogens. If a drug tests negative for carcinogenicity in rodents,
it is unlikely to cause cancer in humans, albeit some rodent carcinogens
are not associated with human cancer. However, many cytotoxic
cancer drugs have the potential to cause cancer; this risk potential is
minimized by their time-limited use in cancer therapy.
THE PHASES OF DRUG METABOLISM
O
O
Xenobiotic metabolizing enzymes have historically been
grouped into those that carry out phase 1 reactions,
which include oxidation, reduction, or hydrolytic reactions,
and the phase 2 reactions, in which enzymes catalyze
the conjugation of the substrate (the phase 1 product)
with a second molecule (Table 6–1). The phase 1
H
N
H
N
H
N
NH
NH
O
O
O