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

genes and 88 pseudogenes in the mouse, and 57 putatively functional
genes and 58 pseudogenes in humans. These genes are grouped,
based on amino acid sequence similarity, into a superfamily composed
of families and subfamilies with increasing sequence similarity.
CYPs are named with the root CYP followed by a number
designating the family, a letter denoting the sub-family, and another
number designating the CYP form. Thus, CYP3A4 is family 3, subfamily
A, and gene number 4.
A Dozen CYPs Suffice for Metabolism of Most Drugs. While several
CYP families are involved in the synthesis of steroid hormones and
bile acids, and the metabolism of retinoic acid and fatty acids (including
prostaglandins and eicosanoids), a limited number of CYPs
that fall into families 1 to 3 are primarily involved in xenobiotic metabolism.
Since a single CYP can metabolize myriad structurally diverse
compounds, these enzymes can collectively metabolize scores of
chemicals found in the diet and environment, and administered as
drugs. In humans, 12 CYPs (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8,
2C9, 2C19, 2D6, 2E1, 3A4, and 3A5) are known to be important for
metabolism of xenobiotics. The liver contains the greatest abundance
of xenobiotic-metabolizing CYPs, thus ensuring efficient first-pass
metabolism of drugs. CYPs are also expressed throughout the GI tract,
and in lower amounts in lung, kidney, and even in the CNS. The
expression of the different CYPs can differ markedly as a result of
dietary and environmental exposure to inducers, or through inter-individual
changes resulting from heritable polymorphic differences in
gene structure; tissue-specific expression patterns can affect overall
drug metabolism and clearance. The most active CYPs for drug metabolism
are those in the CYP2C, CYP2D, and CYP3A sub-families.
CYP3A4, the most abundantly expressed in liver, is involved in the
metabolism of over 50% of clinically used drugs (Figure 6–3A). The
CYP1A, CYP1B, CYP2A, CYP2B, and CYP2E subfamilies are not
significantly involved in the metabolism of therapeutic drugs, but
they do catalyze the metabolic activation of many protoxins and
procarcinogens to their ultimate reactive metabolites.
There are large differences in levels of expression of each CYP
amongst individuals as assessed both by clinical pharmacological
studies and by analysis of expression in human liver samples. This
large inter-individual variability in CYP expression is due to the
presence of genetic polymorphisms and differences in gene regulation
(see following discussion). Several human CYP genes exhibit
polymorphisms, including CYP2A6, CYP2C9, CYP2C19, and
CYP2D6. Allelic variants have been found in the CYP1B1 and
CYP3A4 genes, but they are present at low frequencies in humans
and appear not to have a major role in inter-individual levels of
expression of these enzymes. However, homozygous mutations in
the CYP1B1 gene are associated with primary congenital glaucoma.
CYPs and Drug-Drug Interactions. Differences in the
rate of metabolism of a drug can be due to drug interactions.
Most commonly, this occurs when two drugs
(e.g., a statin and a macrolide antibiotic or antifungal
agent) are co-administered and subjected to metabolism
by the same enzyme. Thus, it is important to determine
the identity of the CYP that metabolizes a particular
drug and to avoid co-administering drugs that are
metabolized by the same enzyme. Some drugs can also
A
CYP1B1
CYP2A6
CYP2B6
CYP2C8/9
CYP2C10
B
CYP1A1/2
CYP2D6
Others
TPMT
Others
CYP2E1
NATs
Esterases
Epoxide
hydrolase
DPYD
CYP3A4/5
GSTs
SULTs
UGTs
Figure 6–3. The fraction of clinically used drugs metabolized by
the major phase 1 and phase 2 enzymes. The relative size of each
pie section represents the estimated percentage of drugs
metabolized by the major phase 1 (panel A) and phase 2 (panel B)
enzymes, based on studies in the literature. In some cases, more
than a single enzyme is responsible for metabolism of a single
drug. CYP, cytochrome P450; DPYD, dihydropyrimidine
dehydrogenase; GST, glutathione-S-transferase; NAT, N-
acetyltransferase; SULT, sulfotransferase, TPMT, thiopurine
methyltransferase; UGT, UDP-glucuronosyltransferase.
inhibit CYPs independently of being substrates for a
CYP. For example, the common antifungal agent, ketoconazole
(NIZORAL), is a potent inhibitor of CYP3A4
and other CYPs, and co-administration of ketoconazole
with an anti-HIV viral protease inhibitor reduces the
clearance of the protease inhibitor and increases its
plasma concentration and the risk of toxicity. For most
drugs, information found on the package insert lists the
CYP that metabolizes the drug and determines the
potential for drug interactions. Some drugs are
CYP inducers that can increase not only their own rates
of metabolism, but also induce metabolism of other
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CHAPTER 6
DRUG METABOLISM