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

140
SECTION I
GENERAL PRINCIPLES
syndrome are unable to detoxify these drugs. Since most
cancer chemotherapeutic agents have a very narrow
therapeutic index, increases in the circulating levels of
the active form can result in significant toxicities. There
are a number of genetic differences in CYPs that can
have a major impact on drug therapy.
Nearly every class of therapeutic agent has been reported to
initiate an adverse drug response (ADR). In the U.S., the annual
costs of ADRs have been estimated at over 100,000 deaths and
$100 billion. It has been estimated that 56% of drugs that are associated
with adverse responses are subjected to metabolism by the
xenobiotic-metabolizing enzymes, notably the CYPs and UGTs.
Since many of the CYPs and UGTs are subject to induction as well
as inhibition by drugs, dietary factors, and other environmental
agents, these enzymes play an important role in most ADRs. Thus,
before a new drug application (NDA) is filed with the Food and
Drug Administration, the route of metabolism and the enzymes
involved in the metabolism must be known. As a result, it is now
routine practice in the pharmaceutical industry to establish which
enzymes are involved in metabolism of a drug candidate and to
identify the metabolites and determine their potential toxicity.
Induction of Drug Metabolism
Xenobiotics can influence the extent of drug metabolism
by activating transcription and inducing the
expression of genes encoding drug-metabolizing
enzymes. Thus, a foreign compound may induce its
own metabolism, as may certain drugs. One potential
consequence of this is a decrease in plasma drug concentration
over the course of treatment, resulting in loss
of efficacy, as the auto-induced metabolism of the drug
exceeds the rate at which new drug enters the body.
Many ligands and receptors participate in this way to
induce drug metabolism (Table 6–5). A particular
Table 6–5
Nuclear Receptors That Induce Drug Metabolism
RECEPTOR
LIGANDS
Aryl hydrocarbon receptor (AHR) Omeprazole
Constitutive androstane receptor Phenobarbital
(CAR)
Pregnane X receptor (PXR) Rifampin
Farnesoid X receptor (FXR) Bile acids
Vitamin D receptor
Vitamin D
Peroxisome proliferator activated Fibrates
receptor (PPAR)
Retinoic acid receptor (RAR) all-trans-Retinoic
acid
Retinoid X receptor (RXR) 9-cis-Retinoic acid
receptor, when activated by a ligand, can induce the
transcription of a battery of target genes. Among these
target genes are certain CYPs and drug transporters.
Thus, any drug that is a ligand for a receptor that
induces CYPs and transporters could lead to drug interactions.
Figure 6–12 shows the scheme by which a drug
may interact with nuclear receptors to induce its own
metabolism.
The aryl hydrocarbon receptor (AHR) is a member
of a superfamily of transcription factors with
diverse roles in mammals, such as a regulatory role in
the development of the mammalian CNS and modulating
the response to chemical and oxidative stress. This
superfamily of transcription factors includes Period
(Per) and Simpleminded (Sim), two transcription factors
involved in development of the CNS, and the
HIF (hypoxia-inducible factor) family of transcription
factors that activate genes in response to low cellular
O 2
levels. The AHR induces expression of genes encoding
CYP1A1, CYP1A2, and CYP1B1, three CYPs that
are able to metabolically activate chemical carcinogens,
including environmental contaminants and carcinogens
derived from food. Many of these substances are inert
unless metabolized by CYPs. Thus, induction of these
CYPs by a drug could potentially result in an increase
in the toxicity and carcinogenicity of procarcinogens.
For example, omeprazole, a proton pump inhibitor used
to treat gastric and duodenal ulcers (see Chapter 45), is
a ligand for the AHR and can induce CYP1A1 and
CYP1A2, with the possible consequences of toxin/
carcinogen activation as well as drug-drug interactions
in patients receiving agents that are substrates for either
of these CYPs.
Another important induction mechanism is due to
type 2 nuclear receptors that are in the same superfamily
as the steroid hormone receptors. Many of these
receptors, identified on the basis of their structural similarity
to steroid hormone receptors, were originally
termed “orphan receptors,” because no endogenous ligands
were known to interact with them. Subsequent
studies revealed that some of these receptors are activated
by xenobiotics, including drugs. The type 2
nuclear receptors of most importance to drug metabolism
and drug therapy include the pregnane X receptor
(PXR), constitutive androstane receptor (CAR), and the
peroxisome proliferator activated receptors (PPARs).
PXR, discovered because it is activated by the synthetic
steroid pregnenolone-16α-carbonitrile, is also activated
by a number of other drugs including, antibiotics
(rifampicin and troleandomycin), Ca 2+ channel blockers
(nifedipine), statins (mevastatin), anti-diabetic drugs