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

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SECTION I
GENERAL PRINCIPLES
co-administered drugs (see later discussion and
Figure 6–12). For example, steroid hormones and
herbal products such as St. John’s wort can increase
hepatic levels of CYP3A4, thereby increasing the
metabolism of many orally administered drugs. Indeed,
St, John’s wort can induce hepatic metabolism of the
steroid components of birth control pills, rendering the
standard dose ineffective in preventing pregancy. Drug
metabolism can also be influenced by diet. CYP
inhibitors and inducers are commonly found in foods
and in some cases these can influence the toxicity and
efficacy of a drug. Components found in grapefruit
juice (e.g., naringin, furanocoumarins) are potent
inhibitors of CYP3A4, and thus some drug inserts recommend
not taking medication with grapefruit juice
because it could increase the bioavailability of the drug.
Terfenadine, a once popular antihistamine, was removed from
the market because its metabolism was inhibited by CYP3A4 substrates
such as erythromycin and grapefruit juice. Terfenadine was
actually a prodrug that required oxidation by CYP3A4 to its active
metabolite, and at high doses the parent compound caused the potentially
fatal arrhythmia torsades de pointes. Thus, as a result of
CYP3A4 inhibition by a co-administered agent, plasma levels of the
parent drug could become dangerously elevated, causing ventricular
tachycardia in some individuals; this led to terfenadine’s withdrawal
from the market. Subsequently, the metabolite was developed as a
drug, fexofenadine, which retains the therapeutic properties of the
parent compound but avoids the step involving CYP3A4.
In addition, inter-individual differences in drug metabolism
are significantly influenced by polymorphisms in CYPs. The
CYP2D6 polymorphism has led to the withdrawal of several clinically
used drugs (e.g., debrisoquine and perhexiline) and the cautious
use of others that are known CYP2D6 substrates (e.g., encainide and
flecainide [anti-arrhythmics], desipramine and nortriptyline [antidepressants],
and codeine).
FLAVIN-CONTAINING
MONOOXYGENASES (FMOs)
The FMOs are another superfamily of phase 1 enzymes
involved in drug metabolism. Similar to CYPs, the
FMOs are expressed at high levels in the liver and are
bound to the endoplasmic reticulum, a site that favors
interaction with and metabolism of hydrophobic drug
substrates. There are six families of FMOs, with FMO3
being the most abundant in liver. FMO3 is able to
metabolize nicotine, as well as H 2
receptor antagonists
(cimetidine and ranitidine), antipsychotics (clozapine),
and anti-emetics (itopride). A genetic deficiency in this
enzyme causes the fish-odor syndrome due to a lack of
metabolism of trimethylamine N-oxide (TMAO) to
trimethylamine (TMA); in the absence of this enzyme,
TMAO accumulates in the body and causes a socially
offensive fish odor. TMAO is found at high concentrations,
up to 15% by weight, in marine animals, where it
acts as an osmotic regulator. FMOs are considered
minor contributors to drug metabolism and they almost
always produce benign metabolites. In addition, FMOs
are not induced by any of the xenobiotic receptors (see
below) or easily inhibited; thus, in contrast to CYPs,
FMOs would not be expected to be involved in drugdrug
interactions. In fact, this has been demonstrated
by comparing the pathways of metabolism of two drugs
used in the control of gastric motility, itopride, and cisapride.
Itopride is metabolized by FMO3 while cisapride
is metabolized by CYP3A4; thus, itopride is less
likely to be involved in drug-drug interactions than is
cisapride. CYP3A4 participates in drug-drug interactions
through induction and inhibition of metabolism,
whereas FMO3 is not induced or inhibited by any clinically
used drugs. FMOs could be of importance in the
development of new drugs. A candidate drug could be
designed by introducing a site for FMO oxidation with
the knowledge that favorable metabolism and pharmacokinetic
properties could be accurately predicted.
HYDROLYTIC ENZYMES
Two forms of epoxide hydrolase carry out hydrolysis of
epoxides, most of which are produced by CYPs. The soluble
epoxide hydrolase (sEH) is expressed in the cytosol
while the microsomal epoxide hydrolase (mEH) is localized
to the membrane of the endoplasmic reticulum.
Epoxides are highly reactive electrophiles that can bind to
cellular nucleophiles found in protein, RNA, and DNA,
resulting in cell toxicity and transformation. Thus, epoxide
hydrolases participate in the deactivation of potentially
toxic metabolites generated by CYPs. There are a
few examples of the influence of mEH on drug metabolism.
The anti-epileptic drug carbamazepine is a prodrug
that is converted to its pharmacologically active derivative,
carbamazepine-10, 11-epoxide by a CYP. This
metabolite is efficiently hydrolyzed to a dihydrodiol by
mEH, resulting in inactivation of the drug (Figure 6–4).
Inhibition of mEH can cause an elevation in plasma concentrations
of the active metabolite, causing side effects.
The tranquilizer valnoctamide and anticonvulsant
valproic acid inhibit mEH, resulting in clinically significant
drug interactions with carbamazepine. This has led to
efforts to develop new anti-epileptic drugs such as
gabapentin and levetiracetam that are metabolized by
CYPs and not by EHs.