CL I N I C A L F R O N T I E R S Drug metabolism

CLINICAL FRONTIERS

Genetic basis of drug metabolism

MARGARET K. MA, MICHAEL H. WOO, AND HOWARD L. MCLEOD

T
he term “pharmacogenetics” was
first coined by Friedrich Vogel1
in 1959, who defined it as the
“study of the role of genetics in drug
response.” It is one of the most rap-
idly growing areas and is becoming
increasingly important in clinical
pharmacy. The pharmacogenetics of
drug-metabolizing enzymes is a
prominent focus of this field, because
genetic makeup is responsible for a
significant portion of drug-induced
toxicity; many drugs are metabolized
by enzymes that are encoded by poly-
morphically expressed genes.2 Geno-
type analysis can be used to identify
DNA changes in specific metabolic
pathways that produce aberrant phe-
notypes. Hence, patients can be clas-
sified as extensive, intermediate, or
poor metabolizers according to their
ability to metabolize certain drugs.
This classification can differentiate
interpatient and intrapatient phar-
macokinetic and pharmacodynamic
variability3-5; however, not all genetic
polymorphisms of drug-metaboliz-
ing enzymes are clinically relevant.
The potential for a clinically signifi-
cant event is enhanced if the drug is
widely used and has a narrow thera-
peutic range, if the enzyme pathway
plays a major role in the elimination
Abstract: The application of pharmacoge-
netics in identifying single nucleotide
polymorphisms (SNPs) in DNA sequences
that cause clinically significant alterations
in drug-metabolizing enzyme activities is
discussed.
Recent advances in pharmacogenomic
research have begun to elucidate the
inherited nature of interindividual differ-
ences in drug-induced adverse reactions,
toxicity, and therapeutic responses. In one
particular area of study, variations in DNA
sequences (i.e., genetic polymorphisms)
explain some of the variability in drug-
metabolizing enzyme activities which con-
tribute to alterations in drug clearance and
impact patients’ response to drug therapy.
Historical and current examples of several
extensively studied SNPs include the genes
encoding for glucose-6-phosphate dehy-
drogenase, N-acetyltransferase, and the su-
perfamily of cytochrome P-450 (CYP) isoen-
zymes. Because CYP isoenzymes metabolize
a large number of structurally diverse drugs
and chemicals, most of the variant geno-
types of the CYP2D6, CYP2C9, CYP2C19, and
CYP3A families have been identified and
of the drug, or if the number of ther-
apeutic alternatives is limited. With
increasing pharmacogenetic evi-
dence, interindividual differences in
drug-related toxicity and therapeutic
response are no longer idiosyncratic.
Although much work is needed to
studied. Individuals with aberrant genes for
these enzymes may experience diminished
efficacy or increased toxicity in response to
certain drugs because of the different levels
of activities associated with variant geno-
types. The frequency of variant alleles for
drug-metabolizing enzymes often differs
among ethnic groups. Continued research
in pharmacogenetics will further our under-
standing in interindividual differences in
drug disposition. The application of this
knowledge will ultimately help individualize
drug dosing and drug therapy selection,
predict toxicity or therapeutic failure, and
improve clinical outcomes.
Pharmacogenetics has elucidated the
genetic basis for interindividual variability
in drug response and will continue to play a
key role in defining strategies to optimize
drug therapy.
Index terms: Antiinflammatory agents; An-
tituberculars; Hydralazine; Hypotensive
agents; Isoniazid; Metabolism; Pharmaco-
genetics; Polymorphism; Race; Sulfona-
mides; Toxicity
Am J Health-Syst Pharm. 2002; 59:2061-9
develop applications of pharmacoge-
netic information for daily patient
care, many success stories illustrate
how pharmacogenetics can be used
to guide therapy. Eventually, phar-
macogenetic information may be-
come a routine tool for providing ra-

MARGARET K. MA, PHARM.D., is Research Associate of Medicine,
Washington University School of Medicine (WUSM), St. Louis, MO,
and Siteman Cancer Center (SCC), St. Louis. MICHAEL H. WOO,
PHARM.D., BCPS, is Research Associate of Molecular Pharmacology,
St. Jude Children’s Research Hospital, Memphis, TN. HOWARD L.
MCLEOD, PHARM.D., is Associate Professor of Medicine, Molecular
Biology and Pharmacology, Genetics, WUSM, and SCC.
Address correspondence to Dr. McLeod at the Department of
Medicine, Washington University School of Medicine, 660 South
Euclid Avenue, Campus Box 8069, St. Louis, MO 63110-1093
(hmcleod@im.wustl.edu).
The work of Drs. Ma and McLeod was supported by grant
CA091842 from the Siteman Cancer Center and by grant GM63340-
01 from the National Institutes of Health.
Copyright © 2002, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/02/1101-2061$06.00.

Am J Health-Syst Pharm—Vol 59 Nov 1, 2002 2061

 CL I N I C A L F R O N T I E R S
tional individualized therapeutics
and patient care.
The pharmacogenetic differences
in a number of phase-I enzymes,
such as cytochrome P-450 (CYP)
isoenzymes, dehydrogenases, and es-
terases, and phase-II (conjugating)
enzymes have been extensively stud-
ied. This review introduces the con-
cept of pharmacogenetics in the con-
text of drug-metabolizing enzymes
and highlights the polymorphisms in
DNA sequences that lead to clinically
significant alterations in drug-
metabolizing-enzyme activities. Many
of these genetic variants (i.e., geno-
types) were discovered after observing
adverse reactions (i.e., phenotypes) af-
ter administering common doses of
drugs to patients. We have focused on
the most common single nucleotide
polymorphisms (SNPs), the inherit-
ed nature of their deficiency, their
frequency, and the clinical impor-
tance of drug-metabolizing-enzyme
variants. Most drug-metabolizing en-
zymes discussed in this review (e.g.,
CYP isoenzymes, N-acetyltransferase)
are located primarily in the liver and,
to a lesser extent, in other organs, such
as the small intestine.
Common terminology
DNA consists of four bases: ade-
nine, guanine, thymine, and cy-
tosine. Any combination of three nu-
cleic acids can form a codon, which is
transcribed into mRNA and translat-
ed into a particular amino acid (e.g.,
ACG encodes for threonine). The
stop codon, TAG, terminates protein
synthesis. An incorrectly placed stop
codon in a gene, caused by mutation,
prematurely truncates an amino acid
chain and may form a nonfunctional
protein. Many of the variations in the
human genome are single base
changes, termed SNPs. A mutation of
one nucleotide of a codon may result
in either a change in the coded amino
acid (nonsynonymous SNP) or no
change (silent polymorphism or syn-
onymous SNP). Since each person
has a pair of each chromosome, he or
2062 Am J Health-Syst Pharm—Vol 59 Nov 1, 2002
Drug metabolism
she has two alleles for each gene, one
on each chromosome. Different al-
leles produce variations in inherited
characteristics, such as eye color and
blood type. In an individual, one
form of the allele (the dominant one)
may be expressed more than another
form (the recessive one). Two identi-
cal alleles result in a homozygous
dominant or homozygous recessive
trait of that gene. A combination of
two different alleles leads to a het-
erozygous trait. One or more genes
that code for a particular protein,
such as an enzyme or a receptor, may
be expressed in different amounts in
different tissues. In this review, all in-
dividual alleles (or genes) are refer-
enced by their gene name (e.g.,
CYP2D6), followed by an asterisk and
an Arabic number (e.g., CYP2D6*1
designates the wild-type allele and
CYP2D6*3 is a mutant allele).6
Glucose-6-phosphate
dehydrogenase
Phenotypes demonstrating varia-
tions in people’s response to certain
drugs were first discovered in the
early 1950s when antimalarial drugs
were found to cause hemolysis in pa-
tients with glucose-6-phosphate de-
hydrogenase (G6PD) deficiency.
G6PD, expressed in all of the body’s
tissues, controls the flow of carbon
through the pentose phosphate
pathway, produces NADPH for re-
ductive biosynthesis, and maintains
oxidation-reduction in the cell to
keep glutathione in a reduced state.7,8
The absence of reduced glutathione
due to G6PD deficiency allows oxi-
dative drugs to oxidize sulfahydroxyl
groups of hemoglobin, leading to
hemolysis. Currently, over two doz-
en drugs, including primaquine, sul-
fones, sulfonamides, nitrofurans, vi-
tamin K analogues, cefotetan, and
chloramphenicol, are known to
cause hemolytic anemia in G6PD-
deficient patients. G6PD deficiency is
a sex-linked (chromosome X) reces-
sive trait and a widespread polymor-
phism, with more than 400 known
variants and affecting more than 400
million people worldwide. However,
the vast majority of affected individ-
uals are asymptomatic. Only 30 dif-
ferent functional mutations in the
gene have been reported, virtually all
of which are found in the region of
the gene that codes for the protein.9,10
All but one are point mutations, with
more than 50% being nucleotide con-
versions from cytosine to guanine.11
The consequence of these genetic
polymorphisms is low G6PD activity,
resulting in reduced glutathione con-
centrations in erythrocytes and subse-
quently clinical manifestation of
hemolytic anemia following the inges-
tion of certain drugs.12
The prevalence of G6PD deficiency
differs among ethnic groups. For in-
stance, males of African and Mediter-
ranean descent more frequently ex-
press the trait. Two types of mutations
are commonly found in Africans,
G6PD A and G6PD A(–). The former
protein produces normal red cell ac-
tivity, while the latter produces only
about 10% of the normal activity and
is unstable in vivo. In patients with
G6PD A, an adenosine-to-guanine
substitution at nucleotide 376
(A376G) mutation causes an aspartic
acid residue to replace an asparagine
residue.13 There are three different
G6PD A(–) variants in one allele. The
A376G mutation occurs in all people,
but the enzyme deficiency is caused
by a second amino acid substitution,
usually a G202A mutation, resulting
in a valine-to-methionine substitu-
tion at codon 68 (Val68Met). Other
mutations are Val690Met and
Val968Met. In Mediterranean peo-
ples, the most common mutation is a
C563T substitution resulting in an
amino acid change (Ser188Phe).
Cases of drug-induced hemolytic
anemia have also been described in
patients treated with cyclosporine,
tacrolimus, penicillin, and cefote-
tan.14 The risk and severity of hemol-
ysis are thought to be associated with
dose, duration of therapy, and other
oxidant stresses, such as infection

and environmental factors. Be-
cause of these confounding factors,
genotyping patients for G6PD defi-
ciency is not warranted, since the
toxicity is rare and not typically
life-threatening and the genotype
does not adequately predict the de-
velopment of hemolytic anemia. For
example, some patients with these
mutations experience toxicity after
drug administration, and others do
not. In addition, the treatment for
drug-induced oxidative hemolytic
anemia is merely cessation of drug
administration, with blood transfu-
sion and corticosteroid administra-
tion warranted in severe cases.
G6PD deficiency is an example of
how genotypic analysis was devel-
oped about half a century after the
clinical observation was made, and
further characterization of the genetic
mutation provided no added clinical
advantages. Although genetic consti-
tution may be at the core of explaining
drug toxicity and efficacy, genotyping
may not always directly affect therapy
or predict patient outcomes.
N-Acetyltransferase
The acetylation polymorphism il-
lustrates another genetic polymor-
phism of a drug-metabolizing enzyme
studied in the early era of pharmaco-
genetics. N-acetyltransferase (gene,
NAT), a phase-II conjugating liver en-
zyme, catalyzes the N-acetylation
(usually deactivation) and O-acetyla-
tion (usually activation) of arylamine
carcinogens and heterocyclic amines.
The slow acetylator phenotype often
experiences toxicity from drugs such
as isoniazid, sulfonamides, procaina-
mide, and hydralazine, whereas the
fast acetylator phenotype may not re-
spond to isoniazid and hydralazine in
the management of tuberculosis and
hypertension, respectively. During the
development of isoniazid, isoniazid
plasma concentrations were observed
in a distinct bimodal population after
a standard dose. Patients with the
highest plasma isoniazid levels were
generally slow acetylators and they
CL I N I C A L F R O N T I E R S
suffered from peripheral nerve dam-
age, while fast acetylators were not
affected.15 Slow acetylators are also at
risk for sulfonamide-induced toxici-
ty and can suffer from idiopathic lu-
pus erythematosus while taking
procainamide.16-18 The slow acetyla-
tor phenotype is an autosomal reces-
sive trait. Studies have shown large
variations of the slow acetylator phe-
notype among ethnic groups: 40–
70% of Caucasians and African-
Americans, 10–20% of Japanese and
Canadian Eskimo, more than 80% of
Egyptians, and certain Jewish popula-
tions are slow acetylators.19,20 In East
Asia, the further north the geographic
origin of the population, the lower the
frequency of the slow acetylator
gene.21-23 The reason for this trend is
unknown, but it has been speculated
that differences in dietary habits or the
chemical or physical environment
may be contributing factors.
Allelic variation at the NAT2 gene
locus accounts for the polymorphism
seen with acetylation of substrate
drugs. There are 27 NAT2 alleles that
have been reported. NAT2 is an un-
usual gene because it consists of
open-reading frames (i.e., protein-
coding regions) with no introns.
Most variant NAT2 alleles involve
two or three point mutations. For ex-
ample, the variant NAT2*5B differs
from the wild-type at three nucle-
otide positions, 341, 481, and 803;
NAT2*6A has two changes at posi-
tions 282 and 590; NAT*13 has one
point mutation at 282; and NAT2*7A
has two changes at positions 282 and
857.18 NAT2*5B and *6A account for
72–75% of all the variant NAT2 al-
leles, which includes at least 94% of
all variant alleles in Caucasians, Japa-
nese, and Hispanics and 83% of the
NAT2 alleles in African-Americans.
NAT2*5B is the most common allele
in Caucasians (40–46%), but occurs
at a very low frequency in Japanese
(0.5%).24-26 NAT*6A, *7B, and *13
share a mutation at C282T. NAT*5A,
*5B, *6A, *7A, *7B, and *13 are asso-
ciated with the slow acetylator phe-
Am J Health-Syst Pharm—Vol 59 Nov 1, 2002
Drug metabolism
notype as a result of a decrease in the
amount of NAT2 protein. The pro-
tein expressed from NAT2*5A, *5B,
and *5C genes has lower activities
than *6A and *7B, whereas *13 has
normal activity.27
Currently, the importance of
these variants in NAT2 is most stud-
ied for their association with a mod-
estly increased risk for cancers, possi-
bly because of prolonged exposure of
the body to chemicals, drugs, or me-
tabolites compared with fast acetyla-
tors.28 A recent preliminary result
suggested that impaired isoniazid
metabolism is associated with point
mutations in NAT2 in a small Japa-
nese population.29 This exciting re-
sult awaits large population studies
to establish clearly the relationship
between the NAT2 genotype and iso-
niazid acetylation. It still takes some
time to establish the clinical utility of
NAT2 genotype analysis to indepen-
dently predict isoniazid acetylation.
However, genotype NAT2 mutations
could be an addition to the tradition-
al therapeutic drug monitoring for
isoniazid in the near future.
Genetic polymorphisms in the
CYP isoenzymes
The CYP isoenzyme superfamily
comprises over 50 heme-containing
proteins that catalyze the oxidative
metabolism of many structurally di-
verse drugs and chemicals. It is one
of the most widely studied drug-
metabolizing-enzyme systems. Its
name is derived from the characteris-
tic maximum spectral absorbance at
450 nm, when it is in its reduced
state. CYP exists as multiple forms or
isoenzymes, with each having vari-
able distribution in different tissues.
The basis for nomenclature is depen-
dent on the similarity among the ge-
netic sequences that encode the
isoenzymes. 30 When the DNA se-
quence of the gene for one CYP
isoenzyme is less than 40% similar to
that of another, the two isoenzymes
belong to different CYP families.
Each enzyme family is represented by
2063
 CL I N I C A L F R O N T I E R S
an Arabic number (e.g., CYP1) and
further divided into subfamilies in
which the isoenzymes’ correspond-
ing DNA sequences are approxi-
mately 70% identical. For example,
CYP1A2 belongs to family 1 and sub-
family A; the last Arabic number in-
dicates a particular gene encoding for
the isoenzyme within the A subfami-
ly. More detailed descriptions of the
CYP nomenclature are found in the
literature.31,32
CYP2D6. CYP2D6 isoenzyme
metabolizes 25–30% of all clinically
used medications, including dex-
tromethorphan, β -blockers (e.g.,
metoprolol), antiarrhythmics, anti-
depressants (e.g., fluvoxamine, flu-
oxetine, imipramine, nortriptyline),
antipsychotics (e.g., haloperidol, ris-
peridone), morphine derivatives,
and many other drugs. Variability in
the interindividual responses to these
agents is often caused by genetic
polymorphisms in CYP2D6, also
termed the debrisoquin/sparteine ge-
netic polymorphism in reference to
the drugs that are its substrates that
led to its discovery. 33 Unlike the
CYP3A family, CYP2D6 is a nonin-
ducible enzyme; thus, its genotype
offers a high predictability of
CYP2D6-mediated metabolism.
CYP2D6, the gene encoding
CYP2D6 isoenzyme, has the most
variations of all genes for CYP isoen-
zymes, with more than 75 allelic vari-
ants identified to date, resulting from
point mutations, single base-pair de-
letions or additions, gene rearrange-
ments, and deletion of the entire
gene. These mutations result in ei-
ther a reduction or complete loss of
activity.34 Administering a CYP2D6
substrate as a probe drug (e.g., bu-
furalol, dextromethorphan, debriso-
quin, sparteine) and measuring the
metabolite-to-parent drug ratio in the
urine (metabolic ratio) differentiate
extensive metabolizers from poor me-
tabolizers. Genotype–phenotype stud-
ies have revealed that poor metaboliz-
ers possess two nonfunctional alleles
and that the phenotype is an autoso-
2064 Am J Health-Syst Pharm—Vol 59 Nov 1, 2002
Drug metabolism
mal recessive trait.35,36 An ultrarapid
metabolizer phenotype has also been
identified and found to result from
gene duplication (up to 13 copies of
CYP2D6).37 Poor metabolizers are
more likely to have adverse effects
from drugs that are substrates of the
isoenzyme and decreased efficacy
from drugs requiring CYP2D6-
mediated activation (e.g., codeine is
converted into morphine by
CYP2D6), while extensive and ul-
trarapid metabolizers may have thera-
peutic failure with drugs activated by
CYP2D6 (e.g., standard antidepres-
sant doses). 38 Because CYP2D6
isoenzyme metabolizes such a large
number of drugs used in the clinical
setting, pharmacists have an impor-
tant role in drug monitoring, includ-
ing identifying CYP2D6 substrates,
monitoring for drug efficacy and
toxicity, and understanding the phe-
notypic and genotypic tools available.
The frequency of the phenotype of
poor metabolizers differs among eth-
nic groups. Less than 1% of Asians,
2–5% of African-Americans, and 6–
10% of Caucasians are poor metabo-
lizers of CYP2D6.4 The most com-
mon variant alleles in Caucasians are
CYP2D6*3, *4, *5, and *6, which ac-
count for about 98% of poor metab-
olizers.39 The CYP2D6*3A allele is a
frameshift mutation caused by a sin-
gle adenine deletion in exon 5 that
results in a premature stop codon.
CYP2D6*4A contains a G-to-A tran-
sition in the last nucleotide of intron
3, producing a splicing defect and
subsequent frameshift in the open-
reading frame and premature stop
codon.40 The CYP2D6*5 variant is
caused by a deletion of the entire
CYP2D6 gene.41 Although poor me-
tabolizers may be homozygous for
one particular defective allele (e.g.,
CYP2D6*4/*4), compound het-
erozygosity (e.g., CYP2D6*4/*6) is
common. Despite a lower frequen-
cy of poor metabolizers, Asian and
African-American populations tend
to have reduced CYP2D6 activity com-
pared with Caucasians because of a
lower occurrence of nonfunctional al-
leles (e.g., *3, *4, *5,*6), but a higher
frequency of alleles associated with re-
duced activity (e.g., *10, *17).42
Genotyping CYP2D6 has been
shown to successfully predict the clear-
ance of fluoxetine, fluvoxamine, de-
sipramine, and mexiletine.43-46 In some
instances, the genotype for CYP2D6
has been useful in predicting adverse
effects associated with antidepressants
and neuroleptics. Arrhythmias, nau-
sea, and vomiting occurred selectively
in poor metabolizers during treatment
with mexiletine, propafenone, and
dexfenfluramine largely because of ele-
vated plasma drug concentrations.46-48
Currently, preliminary dosage recom-
mendations based on CYP2D6 geno-
types are available for antidepres-
sants.49 This gives us a glimpse of how
pharmacogenetics can suggest dose
regimens for a small population of
patients. Prospective studies are war-
ranted to address whether genotype-
based dose recommendations have a
positive outcome on therapy.
CYP2C9. Impaired metabolism of
drugs metabolized by the CYP2C9
isoenzyme, such as phenytoin, S-
warfarin, 50 tolbutamide, losartan,
and nonsteroidal antiinflammatory
drugs (NSAIDs) (e.g., ibuprofen, di-
clofenac, piroxicam, tenoxicam,
mefenamic acid) has been noted.51,52
The CYP2C9 genotype was first
observed to be correlative with the
pharmacokinetics of tolbutamide.
Three allelic variants of the CYP2C9
gene have been identified that are as-
sociated with decreased enzyme ac-
tivity. 52,53 The variant alleles
CYP2C9*2 (Arg144Cys) and *3
(Ile359Leu) contain single nucle-
otide polymorphisms that result in
single amino acid substitutions.
CYP2C9*2 and *3 were associated
with a 5.5- and 27.0-fold decrease in
the intrinsic clearance of S-warfarin,
respectively, compared with the
wild-type allele.54,55 As such, clinical
consequences of the CYP2C9*3 allele
are likely to be more dramatic than
those of CYP2C9*2. Homozygous

CYP2C9*3 alleles were found in poor
metabolizers of phenytoin, glipizide,
tolbutamide, and losartan. Increased
risks of bleeding were observed in
patients with mutant alleles (poor
metabolizers), and subsequent dos-
age adjustments were required.50,56,57
Phenytoin is a substrate of both
CYP2C9 and CYP2C19 isoenzymes,
but CYP2C9 is responsible for its
metabolism to a greater extent; thus,
mutant alleles encoding the CYP2CP
gene have a greater effect on the clini-
cal toxicity of phenytoin. The
CYP2C9*3 mutant allele occurs in ap-
proximately 6–9% of Caucasians and
Asians.52 CYP2C9*2 occurs in approxi-
mately 8–20% of Caucasians and less
frequently in African-Americans and
is virtually absent in Asians. Individ-
uals who require a low dose of war-
farin to maintain optimum anticoagu-
lation have a slightly higher frequency
of variant CYP2C9 alleles than those
who require a higher dose.58 One study
found that life-threatening bleeding
was four times more likely in a group
of patients requiring a lower dose of
warfarin. These patients also had more
difficulty establishing therapeutic anti-
coagulation, which led to multiple vis-
its to the hospital and prolonged hos-
pital stays resulting from serious or
life-threatening bleeding events, and
additional required laboratory test-
ing.56 CYP2C9 genotyping may help
identify high-risk patients who are
candidates for lower warfarin doses,
more frequent monitoring, or alterna-
tive drug treatments.
In addition to the metabolism of
warfarin and phenytoin, polymor-
phisms in CYP2C9 have the potential
to affect the toxicity of several
NSAIDS. For example, homozygous
CYP2C9*3 alleles may result in slow-
er metabolism of these drugs. How-
ever, there have been no reports cor-
relating CYP2C9 genotype to the
pharmacokinetics of NSAIDs. Since
NSAIDs have relatively high thera-
peutic indices, these polymor-
phisms may have less of an impact
on clinical consequences. It is
CL I N I C A L F R O N T I E R S
worth mentioning that a recent
study has elucidated the role of
CYP2C9 genotype on the metabo-
lism of celecoxib, a cyclooxygenase-
2 inhibitor.59 The study found that
patients either heterozygous or ho-
mozygous who have at least one
copy of the CYP2C9*2 (i.e.,
CYP2C9*1/*2 or CYP2C9*2/*2) or
CYP2C9*3 (i.e., CYP2C9*1/*3 or
CYP2C9*3/*3) allele would have an
increased celecoxib plasma area-
under-the-concentration–time curve
as a result of the reduced drug me-
tabolism. The clinical significance of
this observation remains unclear.
CYP2C9 genotyping may affect
the clinical use of warfarin because
of the relatively high prevalence of
poor metabolizers, severe outcomes
as a consequence of drug overdose,
and frequency with which it is pre-
scribed. CYP2C9 genotyping assays
are available only for clinical re-
search, but commercial assays are be-
ing developed.60 Genotype testing for
CYP2C9 will allow pharmacists to
develop dose recommendations to
reduce the risk of adverse drug reac-
tions in patients receiving warfarin
and screen for high-risk patients who
are candidates for lower initial war-
farin doses.56
CYP2C19. CYP2C19 isoenzyme
metabolizes several pharmacologi-
cally important therapeutic agents.
Extensive and poor metabolizers ex-
ist for S-mephenytoin, omeprazole
and other proton-pump inhibitors,
diazepam, propranolol, imipramine,
and amitriptyline. The phenotype
was initially determined using me-
phenytoin as a probe drug because of
the significant correlation between
formation of the 4-hydroxyme-
phenytoin metabolite and the
amount of CYP2C19 in human liver
microsomes. 61 Phenotyping of
CYP2C19 with mephenytoin is limit-
ed because of concerns about the use
of the probe drug, low urinary me-
tabolite concentration, and stability
of the metabolite in urine. More re-
cently, omeprazole and other sub-
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Drug metabolism
strates have been used in phenotyp-
ing studies. The poor metabolizer
phenotype is a result of two non-
functional alleles and is inherited as
an autosomal recessive trait. In con-
trast, the extensive metabolizer phe-
notype consists of both heterozygous
and homozygous dominant geno-
types, but they usually cannot be dis-
tinguished by phenotyping methods.
At least five mutant alleles have
been identified.62 The most common
variant alleles in poor metabolizers,
CYP2C19*2 and *3, arise from single
base-pair substitutions in exons 4
(CYP2C19*3) and 5 (CYP2C19*2)
that introduce premature stop
codons and truncated polypeptide
chains with no functional activity.63
CYP2C19*2 is identified with a 40
base-pair deletion at the beginning of
the exon, which shifts the reading
frame to create an aberrant splice site
and produces a premature stop
codon about 20 amino acids down-
stream.64 CYP2C19*3 is mainly found
in the Japanese population. There are
also ethnic differences in the frequency
of the poor metabolizer phenotype.
About 3–5% of Caucasians and 12–
23% of most Asian populations are
poor metabolizers.65,66
Although relatively few drugs are
metabolized by CYP2C19, pro-
nounced pharmacodynamic effects
tend to be seen in Asians treated with
omeprazole because of the higher
frequency of poor metabolizers.67
Poor metabolizers of mephenytoin
also have higher serum omeprazole–
metabolite ratios than extensive me-
tabolizers because of impaired ome-
prazole metabolism.68 Results of a
study by Furuta et al.69 suggested that
the CYP2C19 genotype might influ-
ence the cure rates for Helicobacter
pylori infection in patients with pep-
tic ulcers. The cure rate was 100% in
poor metabolizers, 60% in patients
with heterozygous genotypes, and
29% in patients with homozygous
wild-types. This may be explained by
the higher accumulation of plasma
omeprazole concentrations in poor
2065
 CL I N I C A L F R O N T I E R S
metabolizers, resulting in a greater
degree of gastric acid suppression.67
Similar to omeprazole, the extent of
lansoprazole and pantoprazole me-
tabolism is highly dependent on
CYP2C19 genotype. Thus, interindi-
vidual differences in plasma concen-
trations of these proton-pump inhibi-
tors may be prospectively predicted by
genetically determined CYP2C19 sta-
tus. However, the contributions of
CYP2C19 isoenzyme to the metabo-
lism of these proton-pump inhibitors
are not evenly distributed; omeprazole
is more extensively metabolized by
CYP2C19 than pantoprazole, lanso-
prazole, and rabeprazole.70
Diazepam is another example of a
CYP2C19 substrate affected by this
polymorphism. The half-life of diaz-
epam in plasma is significantly pro-
longed in individuals who are ho-
mozygous for the mutant CYP2C19*2
allele (80 hours) compared with het-
erozygotes (64 hours) and people with
homozygous wild-type CYP2C19 (20
hours).71,72 Asian populations have
been reported to exhibit slower diaz-
epam metabolism than Caucasians,
possibly due to a higher frequency of
CYP2C19*2 and CYP2C19*3 geno-
types. Poor metabolizers of CYP2C19
may be at a higher risk for diazepam
toxicity, and caution must be exercised
in dosing diazepam.
CYP3A subfamily. CYP3A isoen-
zymes are the predominant subfamily
of CYP enzymes, making it one of the
most important drug-metabolizing
enzymes. The genes for CYP3A isoen-
zymes are expressed primarily in the
liver and small intestines.73,74 Hepatic
CYP3A4 isoenzyme has been esti-
mated to metabolize almost 50% of
currently used drugs as well as en-
dogenous and exogenous corticos-
teroids. Intestinal CYP3A4 isoen-
zyme contributes significantly to the
first-pass metabolism of orally ad-
ministered drugs.75 There is large in-
terindividual variability in genetic
expression for, CYP3A exceeding 30-
fold in some populations,76 but evi-
dence for polymorphic activity has
2066 Am J Health-Syst Pharm—Vol 59 Nov 1, 2002
Drug metabolism
been elusive until recently. Conse-
quently, these variations play a sig-
nificant role in the variability of oral
bioavailability and metabolism of
CYP3A substrates, including HIV
protease inhibitors, benzodiaz-
epines, calcium channel blockers,
hydroxymethylglutaryl coenzyme
A- reductase inhibitors, antineoplas-
tic drugs, nonsedating antihista-
mines, and immunosuppressants.
These variations can result in differ-
ences in drug efficacy and toxicity
among individuals.
CYP3A activities are the sum of
the activities of at least three CYP3A
isoenzymes: CYP3A4, CYP3A5, and
CYP3A7.77,78 Interindividual variabil-
ity due to CYP3A4 activity alone may
vary by up to 50-fold. Functional
consequences of a polymorphism in
the CYP3A4 promoter region
(A290G) (i.e., CYP3A4*1B) have
been studied as a possible cause of
this variability,79-82 but the effects of
this SNP have not been clearly de-
fined. Ethnic variation has been sug-
gested as a possible reason, which
may explain the higher frequency of
the homozygous mutation in Ghana-
ian (51%) than in Scottish Caucasian
(0%) and Saudi populations (1%).83
It is estimated that CYP3A5 isoen-
zyme is only present in 10–30% of
liver samples tested. 84,85 Recently,
CYP3A5 isoenzyme was found to ac-
count for at least 50% of the total
CYP3A content in people who carry
the wild-type CYP3A5*1 allele (96–
98% of the combined population),
suggesting that CYP3A5 may play a
significant role in the metabolism of
CYP3A substrates.86 Only people with
at least one wild-type CYP3A5*1 allele
express large amounts of CYP3A5
isoenzyme, resulting in a 2.5-fold in-
crease in clearance of the probe drug
(midazolam). The most common
cause of loss of the expression of the
CYP3A5 gene in the liver is an SNP at
nucleotide 22,893 in intron 3
(CYP3A5*3), which causes alterna-
tive splicing (exon 3B) and protein
truncation. The CYP3A5*6 allele
contains a G30597A mutation in
exon 7, causing the deletion of exon
7 and reducing CYP3A5 activity.
CYP3A5*1 is more frequently ex-
pressed in non-Caucasian popula-
tions (30% of Caucasians, Japanese,
and Mexicans; 40% of Chinese; and
60% of African-Americans, South-
east Asians, Pacific Islanders, and
Southwestern American Indians);
thus, these populations may metabo-
lize CYP3A substrates more rapidly.86
CYP3A5 appears to be an important
genetic contributor to interindividu-
al and interracial differences in
CYP3A-dependent drug metabolism.
Patients expressing both wild-type
CYP3A4 and CYP3A5 genotypes ex-
tensively metabolize CYP3A sub-
strates, which may lead to a lack of
therapeutic effect. Prediction of drug
interactions involving the inhibition
and induction of CYP3A will contin-
ue to be a challenge and clinically im-
portant because of the diverse role
CYP3A plays in the metabolism of
currently available and future drugs.
However, the variability observed in
CYP3A activity may not be solely due
to polymorphisms in the genes for
these isoenzymes. The recent discov-
ery of the PXR gene, a regulator of CYP
gene expression, provides another
possible factor for the variability in
drug metabolism and a molecular ba-
sis for drug interactions. Identifying
the regulatory mechanisms of enzyme
induction and polymorphisms within
these regulatory elements and high-
throughput screening for future drugs
may allow accurate prediction of
CYP3A enzyme induction and drug–
drug interactions.87-91 Specific guide-
lines for the use of CYP3A pharmaco-
genetics to modulate drug therapy are
under development.
Summary
Major genetic polymorphisms
that affect drug-metabolizing en-
zymes are summarized in Table 1.
The technology to identify SNPs is
available, and databases that house
these SNPs and gene sequence infor-
 CL I N I C A L F R O N T I E R S Drug metabolism

mation are rapidly growing and
readily accessible. In the past, phar-
macogenetics has been used to ex-
plain clinically overt toxicity or the
lack of efficacy in a subset of patients.
As the field continues to develop,
pharmacogenetics will play an im-
portant role in prospectively predict-
ing a patient’s drug activation and
detoxification status, such that a
therapeutic intervention can be
made prior to drug administration
without exposing the patient to drug
toxicity or therapeutic failure. Fur-
ther, recent evidence indicates that
genotyping tests can more accurately
predict a person’s ability to metabo-
lize certain drugs than an approach
based solely on ethnic or geographic
groups.92,93 Although a genetic basis
is preferable to less objective mea-
sures, such as skin color, currently
there is no algorithm that can pro-
vide a comprehensive predictive sur-
rogate for all drug-metabolizing-
enzyme SNPs. Pharmacogenetics has
thus far provided a drug–gene rela-
tionship to drug response and has
contributed in learning how to ad-
minister certain drugs more effec-
tively and safely. As functional con-
sequences of polymorphisms within
drug metabolizing enzymes become
better understood and genotype
analysis becomes less costly, pharma-
cogenetics may lead to the individu-
alization of medication dosing and
improved therapeutics.60
Conclusion
Pharmacogenetics has elucidated
the genetic basis for interindividual
variability in drug response. Pharma-
cogenetics will continue to play a key
role in defining strategies to optimize
drug therapy.
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Table 1.
Genetic Polymorphisms Known To Influence Drug Response
Drugs with
Affected
Enzymea Variant Allele(s) Frequency of PMsb Metabolism Consequence(s) Recommendation
G6PD G6PD A, G6PD A(–) . . . Primaquine, sulfones, Hemolytic anemia Cessation of sulfa
sulfonamides, drugs
nitrofurans, vitamin
K analogues
NAT2 NAT*5B 40–70% of Caucasians Isoniazid, Increased relative risk . . .
and African- sulfonamides, of cancers and drug
Americans procainamide, toxicity
hydralazine
CYP2D6 CYP2D6*2A, 6–10% of Caucasians, β-receptor Lack of analgesic Dosage adjustment
CYP2D6*3, *4, *5, 2–5% of African- antagonists, effects from in PMs
*6, *10, *17 Americans, 1% of antiarrhythmics, codeine, standard
Asians antidepressants, antidepressant
antipsychotics, dosage ineffective
morphine
derivatives
CYP2C9 CYP2C9*2, CYP2C9*3 6–8% of Caucasians Warfarin, phenytoin, Increased bleeding Dosage adjustment
glipizide, episodes from needed for PMs to
tolbutamide, standard warfarin achieve optimal
losartan, NSAIDsc dose, low blood therapeutic
sugar levels in PMs benefit
CYP2C19 CYP2C19*2, 3–5% of Caucasians, S-mephenytoin, Increased omeprazole . . .
CYP2C19*3 12–23% of Asians omeprazole, AUCd and higher H.
diazepam, pylori eradication
propranolol, rate in PMs,
imipramine, prolonged half-life
amitriptyline of diazepam and
increased risk of
diazepam toxicity in
Asians
CYP3A4 CYP3A4*1B Under investigation Under investigation . . . . . .
CYP3A5 CYP3A5*1, CYP3A5*3, Under investigation Under investigation Increased CYP3A5*1 . . .
CYP3A5*6 activity, loss of
CYP3A5*3 activity,
lower CYP3A5*6
activity
a
G6PD = glucose-6-phosphate dehydrogenase, NAT = N-acetyltransferase, CYP = cytochrome P-450 isoenzyme system.
b
PMs = poor metabolizers.
c
NSAIDs = nonsteroidal antiinflammatory drugs.
d
AUC = area-under-the-concentration–time curve.

Am J Health-Syst Pharm—Vol 59 Nov 1, 2002 2067

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