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

AdoMet) as the methyl donor. With the exception of a
signature sequence that is conserved among the MTs,
there is limited conservation in sequence, indicating that
each MT has evolved to display a unique catalytic function.
Although the common theme among the MTs is
the generation of a methylated product, substrate specificity
is high and distinguishes the individual enzymes.
Nicotinamide N-methyltransferase (NNMT)
methylates serotonin and tryptophan as well as pyridinecontaining
compounds such as nicotinamide and nicotine.
Phenylethanolamine N-methyltransferase (PNMT)
is responsible for the methylation of the neurotransmitter
norepinephrine, forming epinephrine; the histamine
N-methyltransferase (HNMT) metabolizes drugs containing
an imidazole ring such as that found in histamine.
COMT methylates the ring hydroxyl groups of neurotransmitters
containing a catechol moiety, such as
dopamine and norepinephrine, in addition to drugs such
as methyldopa and drugs of abuse such as ecstasy
(MDMA; 3, 4-methylenedioxymethamphetamine).
From a clinical perspective, the most important MT may be
thiopurine S-methyltransferase (TPMT), which catalyzes the S-
methylation of aromatic and heterocyclic sulfhydryl compounds,
including the thiopurine drugs azathioprine (AZA), 6-mercaptopurine
(6-MP); and thioguanine. AZA and 6-MP are used for the management
of inflammatory bowel disease (see Chapter 47), as well as
autoimmune disorders such as systemic lupus erythematosus and
rheumatoid arthritis. Thioguanine is used in the treatment of acute
myeloid leukemia, and 6-MP is used worldwide for the treatment of
childhood acute lymphoblastic leukemia (see Chapters 61-63).
Because TPMT is responsible for the detoxification of 6-MP, a
genetic deficiency in TPMT can result in severe toxicities in patients
taking these drugs. When given orally at clinically established doses,
6-MP serves as a prodrug that is metabolized by hypoxanthine guanine
phosphoribosyl transferase (HGPRT) to 6-thioguanine
nucleotides (6-TGNs), which become incorporated into DNA and
RNA, resulting in arrest of DNA replication and cytotoxicity. The
toxic side effects arise when a lack of 6-MP methylation by TPMT
causes a buildup of 6-MP, resulting in the generation of toxic levels
of 6-TGNs. The identification of the inactive TPMT alleles and the
development of a genotyping test to identify homozygous carriers
of the defective allele have now made it possible to identify individuals
who may be predisposed to the toxic side effects of 6-MP therapy.
Simple adjustments in the patient’s dosage regiment have been
shown to be a life-saving intervention for those with TPMT
deficiencies.
ROLE OF XENOBIOTIC METABOLISM
IN THE SAFE AND EFFECTIVE
USE OF DRUGS
Any xenobiotics entering the body must be eliminated
through metabolism and excretion in the urine or
bile/feces. This mechanism keeps foreign compounds
from accumulating in the body and possibly causing
toxicity. In the case of drugs, metabolism normally
results in the inactivation of their therapeutic effectiveness
and facilitates their elimination. The extent of
metabolism can determine the efficacy and toxicity of
a drug by controlling its biological t 1/2
. Among the most
serious considerations in the clinical use of drugs are
ADRs. If a drug is metabolized too quickly, it rapidly
loses its therapeutic efficacy. This can occur if specific
enzymes involved in metabolism are naturally overly
active or are induced by dietary or environmental factors.
If a drug is metabolized too slowly, the drug can
accumulate in the bloodstream; as a consequence, the
pharmacokinetic parameter AUC (area under the plasma
concentration-time curve) is elevated and the plasma
clearance of the drug is decreased. This increase in
AUC can lead to overstimulation or excessive inhibition
of some target receptors or undesired binding to other
cellular macromolecules. An increase in AUC often
results when specific xenobiotic-metabolizing enzymes
are inhibited, which can occur when an individual is
taking a combination of different therapeutic agents and
one of those drugs targets the enzyme involved in drug
metabolism. For example, the consumption of grapefruit
juice with drugs taken orally can inhibit intestinal
CYP3A4, blocking the metabolism of many of these
drugs. The inhibition of specific CYPs in the gut by
dietary consumption of grapefruit juice alters the oral
bioavailability of many classes of drugs, such as certain
antihypertensives, immunosuppressants, antidepressants,
antihistamines, and statins, to name a few.
Among the components of grapefruit juice that inhibit
CYP3A4 are naringin and furanocoumarins.
While environmental factors can alter the steadystate
levels of specific enzymes or inhibit their catalytic
potential, these phenotypic changes in drug metabolism
are also observed clinically in groups of individuals that
are genetically predisposed to adverse drug reactions
because of pharmacogenetic differences in the expression
of xenobiotic-metabolizing enzymes (see Chapter 7).
Most of the xenobiotic-metabolizing enzymes display
polymorphic differences in their expression, resulting
from heritable changes in the structure of the genes. For
example, as discussed earlier, a significant population
was found to be hyperbilirubinemic, resulting from a
reduction in the ability to glucuronidate circulating
bilirubin due to a lowered expression of the UGT1A1
gene (Gilbert’s syndrome). Drugs that are subject to
glucuronidation by UGT1A1, such as the topoisomerase
inhibitor SN-38 (Figures 6–5, 6–7, and 6–8), will display
an increased AUC because individuals with Gilbert’s
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CHAPTER 6
DRUG METABOLISM