The Pharmacogenomics Journal (2008) 8, 4–15
& 2008 Nature Publishing Group All rights reserved 1470-269X/08 $30.00
The clinical role of genetic polymorphisms in
drug-metabolizing enzymes
D Tomalik-Scharte1, A Lazar1,
U Fuhr1 and J Kirchheiner2
1
Department of Pharmacology, Clinical
Pharmacology, University of Cologne, Köln,
Germany and 2Department of Pharmacology of
Natural Products and Clinical Pharmacology,
University of Ulm, Ulm, Germany
Correspondence:
Dr D Tomalik-Scharte, Department of
Pharmacology, Clinical Pharmacology,
University of Cologne, Gleueler Strae 24,
50931 Köln, Germany.
E-mail:dorota.tomalik-scharte@uk-koeln.de
Received 16 August 2006; revised 18 April
2007; accepted 1 May 2007; published
online 5 June 2007
www.nature.com/tpj
REVIEW
For most drug-metabolizing enzymes (DMEs), the functional consequences
of genetic polymorphisms have been examined. Variants leading to reduced
or increased enzymatic activity as compared to the wild-type alleles have
been identified. This review tries to define potential fields in the therapy of
major medical conditions where genotyping (or phenotyping) of genetically
polymorphic DMEs might be beneficial for drug safety or therapeutic
outcome. The possible application of genotyping is discussed for depression,
cardiovascular diseases and thromboembolic disorders, gastric ulcer,
malignant diseases and tuberculosis. Some drugs used for relief of these
ailments are metabolized with participation of genetically polymorphic DMEs
including CYP2D6, CYP2C9, CYP2C19, thiopurine-S-methyltransferase,
dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltrans-
ferase and N-acetyltransferase type 2. Current evidence suggests that taking
genetically determined metabolic capacities of DMEs into account has the
potential to improve individual risk/benefit relationship. However, more
prospective studies with clinical endpoints are needed before the paradigm
of ‘personalized medicine’ based on DME variants can be established.
The Pharmacogenomics Journal (2008) 8, 4–15; doi:10.1038/sj.tpj.6500462;
published online 5 June 2007
Keywords: drug-metabolizing enzymes; pharmacogenetics; genotyping; phenotyping
Introduction
Despite its profound progress, modern pharmacotherapy still faces many
challenges such as adverse drug reactions, sometimes serious or even lethal,
and nonresponse to standard therapy. The observed prominent variability in
individual response to pharmacotherapy, in part, depends on well-known factors
easily assessable, like age, sex, weight, liver and renal function, co-medication,
heterogeneity in the disease, nutritional state or smoking. Furthermore,
inherited variants in drug-metabolizing enzymes (DMEs), transporters, receptors
and molecules of signal transduction cascades may have a major impact on drug
response.
Pharmacogenetics/pharmacogenomics tries to define the influence of genetic
factors on drug efficacy and adverse drug reactions. Whereas pharmacogenetics is
focused on pharmacological consequences of a single gene mutation, pharma-
cogenomics tries to simultaneously consider numerous genes and their mutual
interaction. A major progress in pharmacogenetics/pharmacogenomics has been
possible thanks to the genetic revolution with the human genome project and
the development of modern technologies in genetic testing. It has been expected
that personalized medicine considering patients’ individual genetic profile
 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
5

would soon be introduced into clinical practice. Since
variation in drug concentrations resulting from respective
genetic polymorphisms in DMEs could be directly imple-
mented into dose adjustments, genotyping for DMEs seems
to be the closest to incorporation into clinical practice.1 In
contrast, genotyping for drug transporters and receptors
cannot be recommended as a tool for improvement of drug
therapy in clinical practice at present, and respective gene
tests are not ready for clinical use.2
The importance of genetic variants of DMEs to explain
interindividual differences in drug concentrations and
corresponding pharmacodynamic effects has been recog-
nized about 50 years ago.3 Early examples include the
metabolism of succinylcholine, isoniazid, debrisoquine or
sparteine. Today, the functional consequences of genetic
polymorphisms have been examined for most DMEs.
Variants leading to complete deficiency of enzyme activity
as well as those with reduced or increased activity compared
to the wild-type alleles have been reported. Thus, for a
fraction of drugs, it would be desirable to consider
individual activity of respective DMEs as the basis for
optimizing therapy.
The objective of this article is to critically review the data
on genetic polymorphisms of DMEs with emphasis on
clinical relevance and the level of evidence, in order to
define situations where genotyping or phenotyping might
be beneficial for drug safety or therapeutic outcome. The
data on genetic polymorphisms in DMEs are presented for
several clinically important drug therapies of major medical
conditions (Table 1) and, at the end of each chapter, a short
statement is made on the potential benefit of geno-/
phenotyping in this respective field.
Depression
Pharmacotherapy of depression, one of the major psychia-
tric disorders, is characterized by long duration of drug
therapy, relatively narrow therapeutic index and poor
individual prediction of therapeutic response. According to
the evidence, about 30% of all depression patients do not
respond sufficiently to the first antidepressant drug given.4,5
Failure to respond to antidepressant drug therapy as well as
intolerable side effects not only determine personal suffer-
ing of individuals and their families, but also impose
considerable costs on society. At present, there is no
possibility to reliably predict the individual’s response
before onset of a certain drug treatment.
Tricyclic antidepressants
Many tricyclic antidepressants undergo similar biotransfor-
mation in the liver with CYP2D6 catalyzing hydroxylation
or demethylation reactions.6 CYP2D6 is characterized by a
high interindividual variability in catalytic activity mainly
caused by genetic polymorphisms.7 The respective pheno-
type determined by CYP2D6 genotype is predicted by the
number of functional CYP2D6 alleles, so that the presence
of two, one or no functional CYP2D6-gene copies results in
phenotype of, respectively, rapid or extensive metabolizer

Table 1 Summary of the reviewed medical conditions, respective medicinal treatments and involved genetically polymorphic
drug-metabolizing enzymes

Disease Treatment Drug-metabolizing enzyme/common variant alleles

Depression Tricyclic antidepressants (e.g. amitryptilline, CYP 2D6/CYP2D6*3, *4, *5 and *6 (no enzymatic
imipramine) activity)
Selective serotonin re-uptake inhibitors (e.g. CYP2C19 (for some tricyclic antidepressants)/
paroxetine) CYP2C19*2 and *3 (no enzymatic activity)
Cardiovascular diseases b-blockers (metoprolol, carvedilol) CYP2D6/CYP2D6*3, *4, *5, and *6 (no enzymatic
activity)
AT1 receptor antagonists (losartan, candesartan) CYP2C9/CYP2C9*2 and *3 (decreased enzymatic
activity)
Thromboembolic Coumarin anticoagulants (warfarin, acenocoumarol, CYP2C9/CYP2C9*2 and *3 (decreased enzymatic
disorders phenprocoumon) activity)
Ulcer disease Proton pump inhibitors (e.g. omeprazole, CYP2C19/CYP2C19*2 and *3 (no enzymatic activity)
lansoprazole, pantoprazole)
Malignant diseases Thiopurines (e.g. 6-mercaptopurine, thioguanine) Thiopurine-S-methyltransferase/*2, *3A and *3C (no
enzymatic activity)
5-Fluorouracil Dihydropyrimidine dehydrogenase/exon 14-skipping
mutation in DPYD (unclear contribution of the variant
allele to polymorphic DPD activity in vivo)
Irinotecan Uridine diphosphate glucuronosyltransferase/
UGT1A1*28, UGT1A1*6, UGT1A1*27 (decreased
enzymatic activity)
Tuberculosis Isoniazid N-acetyltransferase type 2/e.g. NAT2*5, *6 and *7
(decreased enzymatic activity)
Abbreviation: DPD, dihydropyrimidine dehydrogenase.

The Pharmacogenomics Journal

 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
6
(EM), intermediate metabolizer (IM) and slow or poor
metabolizer (PM).8,9 Furthermore, inheritance of three or
more functional alleles by gene duplication or gene
amplification determines the ultrafast metabolizer (UM)
phenotype showing higher-than-average enzymatic activ-
ity.9,10 (The situation is even more complex with the
existence of functional but low-activity alleles such as
CYP2D6*10 and influences other than genotype on CYP2D6
activity, but as data on therapeutic consequences of these
factors is very limited, this is not considered here.8–10)
PMs of CYP2D6 have largely (50% or more) decreased
clearance values which was reported for amitriptyline,
clomipramine, desipramine, imipramine, nortriptyline,
doxepin and trimipramine.11
Intuitively, one might expect that individuals to whom
tricyclic antidepressants are prescribed could benefit from
CYP2D6 genotyping if the dose is adjusted for the group of
PMs and UMs of CYP2D6.
In addition to CYP2D6, another highly polymorphic
DME, CYP2C19, also takes part in biotransformation of
some tricyclic antidepressants like amitriptyline, imipra-
mine and clomipramine.12 However, a possible impact of
CYP2C19 polymorphism on the pharmacokinetics of tricyc-
lic antidepressants is by far not so well documented as that
of CYP2D6.
Selective serotonin re-uptake inhibitors (SSRIs)
Some selective serotonin re-uptake inhibitors such as
fluoxetine, fluvoxamine and paroxetine are potent inhibi-
tors of CYP2D6 activity. Therefore, multiple dosing causes
auto-inhibition of CYP2D6 and conversion from extensive
to slow metabolizer phenotype and from ultrafast to
extensive metabolism was described.13,14 In the case of
fluvoxamine, differences in concentration–time curves
(AUCs) between CYP2D6 genotypes were described after
single doses,15,16 whereas multiple doses result in similar
AUCs in PMs and in EMs indicating a strong inhibitory
effect on CYP2D6 in EMs.17
For fluoxetine undergoing enantioselective metabolism
toward the S-enantiomer, impaired demethylation of S-
fluoxetine in CYP2D6 PMs was observed.18 However, since
the metabolite desmethylfluoxetine is also an active anti-
depressant, no clinical implications should be expected with
regard to variable metabolism of fluoxetine as the parent
drug.19 For paroxetine, although it is also a CYP2D6
inhibitor, twofold higher AUCs of the drug were observed
in CYP2D6 PMs than in EMs after multiple doses,20 whereas
and in another study, one UM carrying at least three
functional CYP2D6 gene copies had undetectable drug
concentrations.13 In contrast, no influences of CYP2D6
polymorphisms on pharmacokinetic parameters of sertra-
line and citalopram have been described.
Thus, in conclusion, within the group of SSRIs, CYP
inhibition poses a problem for drug interaction, but the
CYP2D6 gene polymorphism has less effect, and CYP2D6-
based dose adjustments do not seem to be useful for this
group of antidepressants (with the exception of paroxetine).
The Pharmacogenomics Journal
Other antidepressants
For mirtazapine, it could be shown that CYP2D6 genotype
had a significant influence on the variability in the plasma
concentration, however, when comparing UMs to EMs, the
magnitude of concentration differences was only moder-
ate.21
CYP2D6 is responsible for the transformation of venlafax-
ine to the equipotent O-desmethyl-venlafaxine.22–24 Thus,
for mirtazapine and venlafaxine, CYP2D6 influence on
pharmacokinetics is only small and genotyping with sub-
sequent dose adjustments does not seem to be of large
benefit.
The existing data on effects of CYP2D6 polymorphisms on
metabolism of the tetracyclic antidepressant maprotiline is
contradictory.25,26
Finally, CYP2D6 polymorphism seems to have no major
influence on metabolism of nefazodone, moclobemide,
reboxetine and trazodone.27–33
Possible clinical implications
The question whether the differences in pharmacokinetic
parameters caused by genetic polymorphisms in DMEs really
impact the outcome of antidepressant treatment has been
studied in some observational studies. In a German study
evaluating the effect of CYP2D6 genotype on treatment with
CYP2D6-dependent antidepressants, PMs and UMs were
significantly overrepresented as compared to the control
population, respectively, in the group of patients suffering
from adverse drug reactions (fourfold) and nonresponders
(fivefold).34 At the same time, Grasmader et al.35 did not find
any influence of CYP2D6 and CYP2C19 genotype on
antidepressant drug response, although the incidence of
relevant side effects tended to be higher in PMs of CYP2D6.
A high risk for cardiotoxic events and severe arrhythmia was
reported in four patients treated with venlafaxine admitted
to a cardiologic unit who all were CYP2D6 PMs.36 Further-
more, a prospective 1-year clinical study of 100 psychiatric
inpatients suggested a trend toward longer duration of
hospital stay and higher treatment costs in UMs and PMs of
CYP2D6.37
In conclusion, for treatment with antidepressants, there is
extended evidence mainly for CYP2D6 and, to a lower
extent, for CYP2C19 polymorphisms affecting pharmaco-
kinetics of several antidepressants and possibly affecting
therapeutic outcome and adverse drug effects. The useful-
ness of genotyping procedures in depressed patients, how-
ever, has not been confirmed in prospective clinical trials;
therefore, currently this approach is limited to a few
enthusiastic hospitals, such as the Mayo Clinic, and to
some patients with adverse or no therapeutic effects.
However, with the recent approval of pharmacogenetic tests
for CYP2D6 and CYP2C19 by the Food and Drug Adminis-
tration (FDA), a more extensive application of DME-based
personalized therapy in depression may be expected.
Tentatively, before more results of clinical studies are
available, dose adjustments according to pharmacokinetic
differences between genotypes in order to achieve a more
uniform drug exposure may be used.38

Cardiovascular diseases
Cardiovascular diseases are the major cause of morbidity and
mortality in developed countries. For a couple of drugs used
in the therapy of cardiovascular diseases, like some b-
blockers and sartans, clinical implications resulting from
genetic polymorphisms in DMEs are discussed.
b-Blockers
For metoprolol, one of the most often prescribed b-blockers,
the role of CYP2D6 genetic polymorphisms in its pharma-
cokinetics is well established. CYP2D6 catalyzes O-demethy-
lation and, even more specifically, a-hydroxylation of the
drug.39 Metabolism by CYP2D6 showed a slight preference
for the (R)-enantiomer over the pharmacologically active
(S)-enantiomer40 but in both enantiomers, there is a
substantial difference between CYP2D6 EMs and PMs.41,42
Not only metoprolol plasma concentrations but also the
effects on heart rate correlated significantly with CYP2D6
metabolic phenotype.39,43 Kirchheiner et al.44 described the
effects of CYP2D6 genotype on pharmacokinetics of meto-
prolol and heart rate. In UMs carrying the CYP2D6 gene
duplication, total clearance of metoprolol was about 100%
higher compared with EMs (367 versus 168 l/h). These
pharmacokinetic differences were reflected in pharmaco-
dynamics so that the reduction of exercise-induced heart
rate by metoprolol in the UM group was only about half of
that observed in the EMs.
Another b-blocker, the racemate carvedilol, which was the
first to be approved as adjunctive therapy in the treatment
of heart failure, is known to be stereoselectively metabolized
by cytochrome P450 enzymes.45 Whereas b1-antagonism is
primarily conferred by the S-enantiomer of carvedilol, the
R-isoform is responsible for a1-blockade.46 CYP2D6 poly-
morphism has been shown to alter the disposition of
carvedilol enantiomers. PMs demonstrated an impaired
clearance of R-carvedilol, thus being affected by a more
pronounced a1-blockade which might outweigh the bene-
ficial b1-blocking effects.47 Hence, CYP2D6 genotyping
might predict therapeutic outcome in patients with chronic
heart failure treated with carvedilol. However, the inhibition
of CYP2D6 metabolism by administration of fluoxetine in
EMs led to significant changes in plasma pharmacokinetics
in favor of the R-enantiomer without any effects on blood
pressure and heart rate which casts doubt on the clinical
significance of the CYP2D6 genotype for the treatment with
carvedilol in antihypertensive therapy.48
In summary, in our opinion, CYP2D6 genotyping might
be beneficial, if at all, for long-term treatment with
metoprolol in indications such as heart failure or in
post-myocardial infarction patients where no surrogate
parameter such as blood pressure is available to predict
long-term efficacy.
AT1 receptor antagonists (sartans)
AT1 (angiotensin II type 1) receptor antagonists, which are
also used in the treatment of hypertension and congestive
heart failure, are metabolized with involvement of the
Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
7
polymorphic cytochrome P450 enzyme CYP2C9. CYP2C9*2
and CYP2C9*3 are the clinically best-investigated alleles
connected with impaired intrinsic enzymatic activity, how-
ever, the latter, which results in changes in the substrate
binding region of CYP2C9, seems to be of primary
importance.49
Losartan, a potent antagonist of AT1, is metabolized via
CYP2C9 and CYP3A4 to its active metabolite, E-3174.50
McCrea et al.51 described a case of a patient showing a
minimal conversion of losartan to its active metabolite who
was diagnosed as phenotypic PM for CYP2C9 and carrier of
the CYP2C9*3 variant allele. Likewise, in a study of 39
healthy volunteers, the CYP2C9*3 allele was shown to be
associated with decreased formation of E-3174.52 On the
other hand, Lee et al.53 observed no differences in the
pharmacokinetics of losartan and its active metabolite
between subjects with the genotype of CYP2C9*1/*2 and
*1/*3 and those expressing *1/*1. The influence of CYP2C9
polymorphism on pharmacokinetics or the dynamics of
other AT1 receptor antagonists like irbesartan or candesartan
has also been explored. Both drugs are metabolized by
CYP2C9 but in contrast to the pro-drug losartan, they are
the active forms. In patients with the CYP2C9*1/*2 geno-
type, there was a stronger reduction of the diastolic blood
pressure (14.4%) upon therapy with irbesartan as compared
to wild-type carriers (7.5%) and for systolic blood pressure
response, a similar trend was observed.54 Although serum
concentrations of irbesartan were not measured in this
study, it was suggested that the different therapeutic
response in carriers of CYP2C9 variants could be explained
with a slower elimination of irbesartan and, thus, greater
concentrations of the drug. For candesartan, increased
plasma concentrations and decreased clearance of the drug
were described in a patient who was carrier of CYP2C9*1/*3
genotype.55
Further investigations are needed to answer the question
whether genotyping of patients with cardiovascular diseases
before treatment with AT1 receptor antagonists could be
beneficial. Nevertheless, from our point of view, currently
genotyping procedures in that case are not useful.
Thromboembolic disorders
Patients with thromboembolic disorders like pulmonary
embolism or deep vein thrombosis, or those with atrial
fibrillation who are at risk of thromboembolic complica-
tions need acute or sometimes life-long therapy with
anticoagulants. Coumarin anticoagulants, which are vita-
min K antagonists, belong to the most frequently prescribed
drugs in the world and are characterized by a narrow
therapeutic index with both interindividually and intra-
individually varying effectiveness. The possible complica-
tions in therapy with oral anticoagulants involve severe
bleedings or lack of efficacy resulting from, respectively,
over- and underanticoagulation. Genetically polymorphic
CYP2C9 is one of the factors which could affect safety and
efficacy of the treatment with coumarin anticoagulants.
The Pharmacogenomics Journal
 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
8
Warfarin
It is estimated that annually more than 1 million patients in
the United States are treated with warfarin.56 The drug is
administered as a racemic mixture of S- and R-warfarin, with
S-warfarin being 3–5 times more potent than R-warfarin. S-
warfarin is mainly eliminated through 6- or 7-hydroxylation
via CYP2C9 so that the activity of this enzyme influences
mainly the steady-state plasma concentration of S-warfarin
and its antithrombotic activity.57 The appropriate therapy
with warfarin and other oral anticoagulants of the coumarin
type is based on evaluating international normalized ratio
(INR), which is normalized prothrombin time.
It could be shown that plasma clearance of S-warfarin, but
not the clearance of R-warfarin, depends significantly on
CYP2C9 genotype, although nongenetic factors may also
contribute to the great interindividual variability in this
parameter.58 Moreover, for patients with at least one variant
allele CYP2C9*2 or CYP2C9*3, a longer induction period to
achieve a stable warfarin dosing and an increased risk of INR
values above the reference range along with a higher risk of
life-threatening bleedings were observed.59 Carriers of the
CYP2C9 variant alleles were also considerably overrepre-
sented in the group of patients requiring lower maintenance
doses of warfarin.60 As a result, it was suggested that CYP2C9
genotyping may select a population of patients who are
potentially at the risk of complications associated with
warfarin therapy.59,60
Acenocoumarol
Acenocoumarol, the 40 -nitro analog of warfarin, is also
administered as a racemic mixture of R- and S-enantiomers
and like for warfarin, the metabolism of its S-enantiomer is
predominantly mediated by CYP2C9. In contrast to warfar-
in, the anticoagulation potencies of the R- and S-aceno-
coumarol are similar, although the mean oral clearance of
S-acenocoumarol is essentially greater and its elimination
half-life is far shorter than that of the R-enantiomer.61
Consequently, R-acenocoumarol makes the major contribu-
tion to the overall anticoagulation effect.
Results of clinical studies dealing with the role of CYP2C9
polymorphisms in the anticoagulation effect of acenocou-
marol are partly contradictory. Whereas some studies
showed a considerable effect of CYP2C9 genotype only in
patients with at least one CYP2C9*3 allele,62,63 recent data
showed that acenocoumarol patients carrying at least one
CYP2C9*3 or CYP2C9*2 allele were at the risk of having INR
of six or higher and suffering from major bleeding
complications.64,65 Moreover, a clear genotype–dose rela-
tionship was found in this study so that significant smaller
doses of acenocoumarol were suggested for carriers of the
CYP2C9 mutant alleles as compared with the wild-type
patients.
Phenprocoumon
The influence of CYP2C9 polymorphisms on pharmaco-
kinetics and dynamics of phenprocoumon, another warfarin
analog which is favored in a few European countries, was
addressed in several clinical studies. Whereas clearance of
The Pharmacogenomics Journal
S-phenprocoumon tended to decrease with the increasing
number of CYP2C9*2 and *3 alleles, no influence of both
CYP2C9 variants on R-phenprocoumon pharmacokinetic
parameters was detected.66
Although Visser et al.64,65 could not find significant
differences with respect to INR or major bleeding complica-
tions between carriers of CYP2C9 variant genotypes and
wild-types, results of other studies support the role of
CYP2C9 genetic polymorphism in patients treated with
phenprocoumon. Hummers-Pradier et al.67 found an in-
creased risk of hemorrhage in phenprocoumon patients
carrying the CYP2C9*3 allele, but not the CYP2C9*2 allele.
However, in another study presenting data of 284 phenpro-
coumon patients, both mutant alleles CYP2C9*3 and
CYP2C9*2 were related to an increased risk of overanticoa-
gulation.68
As this review focuses on genetic polymorphisms in
DMEs, here we only want to mention briefly the importance
of genetic polymorphisms affecting the activity of the
vitamin K epoxide reductase complex subunit 1 (VKORC1),
which is the target molecule of coumarin anticoagulants, in
the antithrombotic therapy. In many clinical trials which
have been published recently, it could be shown that
VKORC1 genetic polymorphisms also explain a large part
of the variability in dose requirements of vitamin K
antagonists and therefore, in addition to CYP2C9 poly-
morphism and demographic factors, play a dominant role in
the determination of individual dose.69–71 Moreover, Sconce
et al.69 proposed a dosing algorithm for individual adjust-
ment of warfarin dose taking into account the CYP2C9 and
VKORC1 genotype, age and height, however, such approach
should be proved in prospective clinical studies before wide
clinical implementation is possible.
Although genetic testing for CYP2C9 and VKORC1
polymorphisms could not replace the role of INR in dose
adjustment of coumarin anticoagulants, this procedure
certainly may help to identify a group of patients tending
toward a longer induction period to achieve a stable dosing
and who are potentially at a higher risk of serious bleeding
complications.
Ulcer disease and proton pump inhibitors
Proton pump inhibitors (PPIs), such as omeprazole, esome-
prazole, lansoprazole, pantoprazole or rabeprazole, are
commonly prescribed in a combination with antibiotics
for Helicobacter pylori eradication in patients with gastric and
duodenal ulcer disease. PPIs undergo extensive presystemic
biotransformation in the liver with the involvement of
genetically polymorphic CYP2C19. CYP2C19*2 and
CYP2C19*3 are the most common nonfunctional alleles
which are responsible for the majority of PM phenotypes of
CYP2C19.72
Anderson et al.73 observed that in PMs of mephenytoin (a
model substrate of CYP2C19) the AUC for omeprazole,
lansoprazole and pantoprazole at steady state was fivefold
higher compared with EMs indicating that approximately

80% of the dose for all three PPIs is metabolized by
CYP2C19. For different PPIs, drug exposures defined using
AUC values were 3- to 13-fold higher in PMs and about 2- to
4-times higher in heterozygous EMs as compared to
homozygous EMs of CYP2C19.74 At the same time, the
elevation of intragastric pH as a pharmacodynamic response
to PPIs was related directly to the respective AUC and a
much higher pH was observed over 24 h following the
administration of PPIs in PMs than in EMs.74
In a systematic review on pharmacogenetic studies with
PPIs, Chong and Ensom75 evaluated the effects of CYP2C19
genetic polymorphism on the clinical outcomes, that is, H.
pylori eradication rates upon therapy with these drugs. The
results of the most studies supported the hypothesis that
eradication rates vary with CYP2C19 genotype and in PMs, a
significantly better efficacy of PPIs was observed. The
authors pointed out that only in a few studies, notably
performed with rabeprazole, a similar cure rate irrespective
of CYP2C19 genotype was demonstrated. However, rabepra-
zole undergoes mainly nonenzymatic metabolism and
CYP3A4 in addition to CYP2C19 contribute to the enzyma-
tically mediated fraction of its biotransformation.76 Never-
theless, in a clinical study determining a cure rate of H. pylori
infections upon dual rabeprazole/amoxicillin therapy in
relation to CYP2C19 genotype status in Japanese patients,
significant differences between homozygous and hetero-
zygous EMs and PMs were noticed (cure rates were 60.6, 91.7
and 93.8%, respectively).77
In another study, Furuta et al.78 investigated the impact of
CYP2C19 genotype on eradication rates of H. pylori upon
triple therapy comprising PPI, clarithromycin and amox-
icillin. These rates were 72.7, 92.1 and 97.8% in the
homozygous extensive, heterozygous extensive and PMs,
respectively. The authors confirmed that CYP2C19 genotype
seems to be one of the important factors associated with
cure rates. Moreover, the same authors could also demon-
strate the significance of CYP2C19 genotype for eradication
upon dual therapy (amoxicillin as the only antibiotic and
high doses of omeprazole) showing cure rates of 100% in
PMs.79 For that reason, the authors concluded that in
Japanese patients homozygous for CYP2C19 defect alleles,
the dual therapy might be sufficient. Furuta et al.80 also
suggested that CYP2C19 genotyping test could be a useful
tool for deciding on the optimal treatment regimen with
PPIs, including a dual (PPI plus antibiotic) or a triple (PPI
plus two antibiotics) therapy.
The role of CYP2C19 polymorphism for eradication of
H. pylori was also studied in the Caucasian population.
However, in contrast to the Asian population, the preva-
lence of PM of CYP2C19 in Caucasians is much lower, that
is, about 2.8 versus 21.3%, respectively, in Caucasians and
Japanese.81 Schwab et al.82 could show significant differ-
ences considering the efficacy of lansoprazole-based
quadruple therapy between Caucasian patients carrying
wild-type alleles, one and two CYP2C19 defect alleles with
cure rates of 80.2, 97.8 and 100% in the respective groups.
The authors concluded that eradication rates of H. pylori
highly depend on CYP2C19 genotype in white patients if
Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
9
the standard doses of lansoprazole are administered within
this regimen and carriers of CYP2C19 wild-type allele might
benefit from a higher PPIs dosage.
In contrast to these results, the authors of the recently
issued meta-analysis evaluating the impact of CYP2C19
polymorphism on H. pylori eradication rates in dual and
triple therapies with PPIs concluded that only therapies
based on omeprazole undoubtedly depend on CYP2C19
genotype while those with lansoprazole and rabeprazole do
not.83 They suggested that genotyping for CYP2C19 could
be of greater importance only for the long-term PPI
antisecretory therapies in which CYP2C19 impact would
be more profound.
In summary, according to the results of numerous clinical
studies, CYP2C19 polymorphisms is an important factor
affecting the pharmacokinetics of most PPIs, values of
intragastric pH and eradication rates of H. pylori. Therefore,
in our opinion, genotyping for CYP2C19 polymorphisms
could be recommended, first of all in Asian populations
characterized by a high prevalence of defect CYP2C19
alleles. The intuitive consequence of this approach would
be a higher dosage in the group of EMs and/or an adjusted
treatment regimen. The results of prospective controlled
clinical trials need to be awaited to see whether patients
might benefit from such individually tailored therapy.
Malignant diseases
Most anticancer drugs are characterized by a very narrow
therapeutic index and severe consequences of over- or
underdosing in the form of, respectively, life-threatening
adverse drug reactions or increased risk of treatment
failure. Polymorphisms in genes encoding DMEs are con-
sidered to be an important factor contributing to individual
drug response in patients undergoing antineoplastic
chemotherapy.
Thiopurines
Thiopurines, such as 6-mercaptopurine and thioguanine are
largely used in the treatment of acute leukemia whereas
rheumatoid arthritis is a common field of application for the
immunosuppressant azathioprine. These drugs, following
their activation to thioguanine nucleotides via the purine
salvage pathway, are incorporated into DNA.84 At the same
time, thiopurine-S-methyltransferase (TPMT) inactivates
thiopurine drugs. The individual enzymatic capacity is
inherited as an autosomal codominant trait resulting in
three distinct phenotypes which show a pronounced ethnic-
specific distribution.85 Approximately 89% of Caucasians
demonstrate a high catalytic TPMT activity while about 11
and 0.3%, respectively, of that population exhibit an
intermediate and low activity.86 The molecular basis of such
interindividual variation is provided by genetic polymorph-
isms and the alleles *2, *3A and *3C explain about 80–95%
of altered enzyme activity.87 Impaired TPMT activity is
inversely correlated with the generation of thioguanine
nucleotides which are responsible for toxicity.88,89 Myelo-
toxicity is the dose-limiting toxicity of thiopurines, and this
The Pharmacogenomics Journal
 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
10
adverse event may necessitate discontinuation of therapy
and can even lead in fatal outcomes in patients with low
TPMT activity if treated with conventional doses.90,91 TPMT
genotyping predicts the clinical phenotype with almost
complete concordance (at least 95%) and essentially all
homozygous carriers of defective alleles are affected by toxic
side effects that require discontinuation of therapy.90,92
However, in analysis of 41 patients with Crohn’s disease and
azathioprine-related hematotoxicity, early onset of intoler-
ance in carriers of mutant TPMT alleles was indeed observed
but genetic variants could explain only 27% of all toxic
cases.93 Hepatic TPMT activity can reliably be determined by
measurement of the catalytic activity of cytosolic TPMT in
erythrocytes using established radiochemical or high-per-
formance liquid chromatography (HPLC) methods.94,86
However, several cases of shortcomings of such TPMT
phenotyping approaches have been reported. TPMT-defi-
cient patients spuriously exhibited a normal enzyme activity
after they had received erythrocyte concentrates of homo-
zygous wild-type donors.90,95 Moreover, the phenotyping
results can also be significantly influenced by concomitant
therapy with furosemide, sulfasalazine, salicylic acid, intake
of certain foodstuff and the presence of uremia.96,97
For patients treated with thiopurines, an individualized
therapy with regard to TPMT genotype has been suggested.
Reduction of doses to 5–10% of conventional average doses
in carriers of two nonfunctional TPMT alleles has been
shown to allow for an efficacious continuation of ther-
apy.87,98,99 For patients heterozygous for defective TPMT
alleles, a full starting dose has been recommended taking
into account that a dose reduction to avoid toxicity will be
probably required.99
In conclusion, present genotyping or phenotyping strate-
gies predict individuals being deficient with respect to TPMT
at high accuracy and should routinely precede the onset of
therapy with thiopurine-derived drugs in order to minimize
life-threatening and cost-intensive myelotoxic adverse
events. For 6-mercaptopurine, which is widely used for
therapy of acute lymphoblastic leukemia in children, the
FDA has implemented respective pharmacogenetic data into
the product label, considering the impact of TPMT genotype
on severe toxicity as well as the availability of genotypic and
phenotypic testing.
5-Fluorouracil
The initial and rate-limiting enzyme in the hepatic meta-
bolism of the chemotherapeutic agent 5-fluorouracil (5-FU)
is dihydropyrimidine dehydrogenase (DPD), thus affecting
its pharmacokinetics, efficacy and toxicity.100–102 Applica-
tion of 5-FU is restricted by a narrow therapeutic index and
could be complicated by severe toxicity of WHO grade III–IV
with symptoms like mucositis and granulocytopenia.103
Moreover, severe adverse events have also been observed
with capecitabine, which is an orally bioavailable prodrug
of 5-FU.104
Three-to-five percent of Caucasians have been reported to
show a reduced enzymatic activity potentially leading to
severe 5-FU-related toxicity in cancer patients.105 However,
The Pharmacogenomics Journal
measuring individual DPD activity in peripheral mono-
nuclear blood cells does not provide a valid phenotyping
approach since the correlation with hepatic DPD activity
and 5-FU-pharmacokinetics is poor.106,107
Polymorphisms within the human DPD gene (DPYD) have
been associated with DPD deficiency and severe 5-FU-related
toxicity in cancer patients. One of the best-described
polymorphisms is the so-called exon 14-skipping mutation
at the 50 -splice donor site of exon 14 which is present at a
prevalence of only 1% in the Caucasian population but has
been detected in 24% of patients suffering from WHO grade
IV toxicity upon treatment with 5-FU.108 To identify
patients at increased risk for severe 5-FU-induced toxicity,
routine screening for the exon 14-skipping mutation before
onset of chemotherapy has been recommended.109 How-
ever, the predictive relevance of genotyping for this
mutation is still controversially discussed since the geno-
type–phenotype correlation is apparently incomplete.110
In a study in patients who had suffered from severe
toxicity owing to treatment with 5-FU, direct sequencing of
all exons revealed possible genetic causes in 8 out of 14
subjects. Six of them were heterozygous carriers of the exon
14-skipping mutation.111 Screening for known mutations in
a cohort of cancer patients undergoing 5-FU chemotherapy
explained a low DPD activity phenotype only in 17% of all
cases and the sole carrier of the exon 14-skipping mutation
was inconspicuous with regard to enzyme activity.105 More-
over, the sample sizes of the previous studies are virtually
too small to dare a valid estimation of the clinical value of
DPYD genotyping in order to prevent 5-FU-related toxicity.
Currently, the predictive value of genotyping of DPYD for
individualized anticancer therapy needs further elucidation
in large prospective studies.
Irinotecan
Recently, much attention has been paid to importance of
pharmacogenetic polymorphisms in uridine diphosphate
glucuronosyltransferase (UGT) and its role in toxicity and
therapeutic response in cancer patients undergoing treat-
ment with the potent antitumor agent irinotecan. SN-38,
the active metabolite of irinotecan and topoisomerase I
inhibitor, is glucuronidated to its inactive form by UGT1A1,
the UGT enzyme which is also responsible for glucuronida-
tion of bilirubin.112 Several variant alleles leading to reduced
enzymatic UGT1A1 activity have been identified in the
UGT1A1 gene. These polymorphisms become manifest as
unconjugated hyperbilirubinemia in the form of Crigler–
Najjar or Gilbert’s syndromes as well as, in patients treated
with irinotecan, they result in reduced SN-38 glucuronida-
tion rates.113 For UGT1A1 genetic variations, major inter-
ethnic differences have been shown; whereas UGT1A1*28
promoter polymorphism (TA repeat in the promoter) is
quite common in the Caucasian population, UGT1A1*6 and
UGT1A1*27 situated in the coding region of UGT1A1 are
found mainly in Asians.114
Impact of UGT1A1 polymorphisms on irinotecan toxicity,
which is characterized by severe diarrhea and neutropenia,
has been studied in several retrospective as well as

prospective studies. It could be shown that the presence of
common UGT1A1 mutant alleles, even in heterozygous
carriers, significantly changed the disposition of irinotecan
causing severe toxicity in patients.114–116 Consecutively,
genotyping for UGT1A1 polymorphisms before therapy with
irinotecan was recommended for patients of all ethnic
groups. If UGT1A1 genotyping is not possible, total bilirubin
level was proposed as an easy surrogate parameter for
prediction of life-threatening toxicity due to irinotecan,115
however, usefulness of this approach should definitely be
confirmed in further clinical trials. Finally, given the
cumulative evidence, the FDA has approved a new labeling
for irinotecan in favor of UGT1A1*28 genotyping, which
reflects the prevalence of the UGT1A1*28 allele in European
Americans. A reduced initial dose of irinotecan has been
recommended for homozygous carries of this variant allele
as they are at increased risk for neutropenia (FDA, http://
www.fda.gov).
In summary, importance of individually tailored medicine
for cancer patients seems to be of critical importance to
develop safe and effective chemotherapy. Even if genetically
polymorphic DMEs are not the only factor contributing to the
wide interindividual variation in toxicity and efficacy of
anticancer drugs, the recent implementation of the pharmaco-
genetic data to the product labels of 6-mercaptopurine
and irinotecan can be assessed as milestones in oncology
and pharmacogenetics.117 However, successful implementa-
tion of pharmacogenetic tests in cancer patients would
depend on thorough analysis of clinical benefits and cost
effectiveness of this approach.
Tuberculosis and isoniazid
Tuberculosis is still a global emergency, first of all due to the
growing prevalence of drug resistant Mycobacterium tubercu-
losis strains and the spread of AIDS infection.118 Isoniazid is
a pivotal agent in the treatment of tuberculosis in combina-
tion with other drugs, or alone as a prophylactic agent. It
is metabolized to acetylisoniazid by the hepatic enzyme
N-acetyltransferase type 2 (NAT2). The enzyme is target of
genetic polymorphisms and carriers of at least one wild-type
allele (NAT2*4) or a high-activity variant allele (NAT2*12)
demonstrate high NAT2 activity (rapid acetylator, RA),
whereas slow acetylators (SA) have two low-activity variants.
Subjects with one high-activity NAT2 allele are sometimes
classified as intermediate acetylators (IA). Pronounced
interethnic differences in the prevalence of the rapid- and
slow-acetylation phenotype have been observed with the
highest frequencies of RAs in East Asia (about 58–90%)
followed by other parts of Asia and Europe (between 32 and
43%) and the lowest frequencies found in Africa.119,120
Isoniazid was the first NAT2 substrate for which acetyla-
tion polymorphism with its well-known bimodal distribu-
tion was described following the observation that peripheral
neuropathy, a potential side effect of the drug, is subject to
interindividual variation depending on patients’ acetylation
capacity.121 Tiittinen et al.122 could demonstrate that the
Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
11
metabolism of isoniazid varies interindividually, with mean
apparent elimination half-lives of 80 min for rapid acetyla-
tors and 180 min for slow acetylators. Subsequently, these
earlier findings were complemented by genotyping studies
showing a linear relationship of isoniazid pharmaco-
kinetic parameters to the number of highly active NAT2
genes.123–125 According to Kinzig-Schippers et al.,125 indivi-
dual isoniazid clearance could be predicted as clearance
(l/h) ¼ 10 þ 9  number of NAT2*4 alleles.
At the same time, it was observed that occurrence of
adverse effects upon isoniazid therapy is dependent on
NAT2 activity, too. In SAs, hepatic toxicity, neurotoxic
effects and systemic lupus erythematodes seem to appear
more frequent and have more severe course than in
phenotypic RAs.126 These observations have also been
supported by later genotyping studies. In tuberculosis
patients treated with isoniazid and rifampicin, a significant
association between hepatotoxicity and NAT2 genotype was
observed so that compared with patients with two highly
active NAT2 alleles, the relative risk was 4 for patients with
one highly active NAT2 allele and 28 for patients with no
highly active NAT2 allele. The authors suggested that NAT2
genotyping before therapy could be useful.127 Likewise,
Huang et al.128 could show in a study in 224 tuberculosis
patients that carriers of no highly active NAT2 alleles had a
higher risk for hepatotoxicity than those with at least one
highly active NAT2 allele, that is, 26 versus 11%. Further-
more, hepatic injury in SAs is more likely to have severe
course than in RAs. On the other hand, efficacy of isoniazid
therapy seems to be better in SAs and significant differences
in the mean early bactericidal activity of isoniazid between
homozygous SAs and heterozygous or homozygous RAs
could be demonstrated.129
Individually tailored therapy with isoniazid, which could
warrant optimal therapeutic efficiency and limitation of
toxic effects, has not been used in clinical routine so far,
although reliable genotyping or phenotyping approaches
are available.
Currently, potential benefits of isoniazid dose adjustment
according to NAT2 genotype in tuberculosis patients are
being assessed in two large European (‘IDANAT2’) and East
Asian studies with participation of the authors of this review
in the former. The studies test the hypotheses that by means
of adjustment of the isoniazid dose, early treatment failure
can be reduced twofold in RAs whereas in SAs hepatotoxicity
can be reduced threefold. IDANAT2 has a prospective,
randomized, controlled and double-blind design (Figure 1)
and should provide a definite answer on dose individualiza-
tion according to genotype of a DME in this disease of global
importance.
Perspectives
Thousands of manuscripts addressing pharmacogenetic
questions in in vitro studies and clinical trials with healthy
volunteers or patients have been published in the past
decades. Even so, it seems that the way to a broader use of
The Pharmacogenomics Journal
 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
12
Figure 1 Scheme of a prospective, double-blind, multicenter, parallel group randomized trial to evaluate the possible benefit of isoniazid dose
adjustment according to the genotype of N-acetyltransferase type 2 (IDANAT2).
genotyping/phenotyping approaches for DMEs at the pa-
tients’ bedside and, consequently, implementation of the
respective results in the form of personalized pharmaco-
therapy is quite laborious. There are some possible reasons
for this slow progress in clinical pharmacogenetics/pharma-
cogenomics. Thanks to modern pharmacogenomic technol-
ogies, it was found that genetic regulation of DMEs, like
other proteins controlling biological processes in living
organisms, is actually more complex than initially expected.
In reality, gene function is not a constant but it varies
depending on environmental factors as well as gene
expression could be affected by respective gene products
themselves.130 For that reason, there is no exact relationship
between the genotype and phenotype, that is, the actually
measured activity of DMEs, although in many cases the
genotype explains most of the interindividual variability.
Another essential problem is the lack of prospective clinical
studies assessing the merits of genotyping/phenotyping
strategies for personalized medicine in large numbers of
patients. Similarly, no reliable data on cost effectiveness of
such screening procedures exist. A successful implementa-
tion of individually tailored medicine would depend not
only on further improvement in multigenic testing but also
needs to be preceded by numerous prospective studies with
clinical endpoints.
In summary
We reviewed the main genetic polymorphisms of DMEs and
discussed their potential clinical relevance on pharmaco-
logical therapies of common human ailments, with the
intention to demonstrate the importance of pharmaco-
genetic factors for drug toxicity and treatment efficacy
in patients. Although interindividual variability in drug
response is also caused by many nongenetic factors and the
The Pharmacogenomics Journal
respective genetic factors are probably far more complex
than was initially assumed, already today there is a solid
place for genotyping for DMEs in some therapies. However,
more prospective studies with clinical endpoints are needed
before the paradigm of ‘personalized medicine’ based on
DME variants can be established.
Duality of Interest
No conflict of interest exists with any of the authors.
References
1 Kirchheiner J, Sasse J, Roots I, Brockmoller J, Bauer M. The value of
pharmacogenetic tests in antidepressive medication therapy. Nerve-
narzt 2005; 76: 1340–1354.
2 de Leon J, Armstrong SC, Cozza KL. Clinical guidelines for psychiatrists
for the use of pharmacogenetic testing for CYP450 2D6 and CYP450
2C19. Psychosomatics 2006; 47: 75–85.
3 Kalow W. Familial incidence of low pseudocholinesterase level. Lancet
1956; 2: 576–577.
4 Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ. World
federation of societies of biological psychiatry (WFSBP) guidelines for
biological treatment of unipolar depressive disorders part 1: acute and
continuation treatment of major depressive disorder. World J Biol
Psychiatry 2002; 3: 5–43.
5 Nelson JC. Managing treatment-resistant major depression. J Clin
Psychiatry 2003; 64(Suppl 1): 5–12.
6 Baumann P, Jonzier Perey M, Koeb L, Küpfer A, Tinguely D, Schopf J.
Amitriptyline pharmacokinetics and clinical response: II. Metabolic
polymorphism assessed by hydroxylation of debrisoquine and mephe-
nytoin. Int Clin Psychopharmacol 1986; 1: 102–112.
7 Bertilsson L, Dahl ML, Dalen P, Al-Shurbaji A. Molecular genetics of
CYP2D6: clinical relevance with focus on psychotropic drugs. Br J Clin
Pharmacol 2002; 53: 111–122.
8 Sachse C, Brockmoller J, Bauer S, Roots I. Cytochrome P450 2D6
variants in a Caucasian population: allele frequencies and phenotypic
consequences. Am J Hum Genet 1997; 60: 284–295.
9 Zanger UM, Fischer J, Raimundo S, Stuven T, Evert BO, Schwab M et al.
Comprehensive analysis of the genetic factors determining expression

D Tomalik-Scharte et al
and function of hepatic CYP2D6. Pharmacogenetics 2001; 11:
573–585.
10 Griese EU, Zanger UM, Brudermanns U, Gaedigk A, Mikus G, Morike K
et al. Assessment of the predictive power of genotypes for the in-vivo
catalytic function of CYP2D6 in a German population. Pharmaco-
genetics 1998; 8: 15–26.
11 Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J, Roots I et al.
Pharmacogenetics of antidepressants and antipsychotics: the con-
tribution of allelic variations to the phenotype of drug response. Mol
Psychiatry 2004; 9: 442–473.
12 Brosen K. Some aspects of genetic polymorphism in the biotransfor-
mation of antidepressants. Therapie 2004; 59: 5–12.
13 Lam YW, Gaedigk A, Ereshefsky L, Alfaro CL, Simpson J. CYP2D6
inhibition by selective serotonin reuptake inhibitors: analysis of
achievable steady-state plasma concentrations and the effect
of ultrarapid metabolism at CYP2D6. Pharmacotherapy 2002; 22:
1001–1006.
14 Laine K, Tybring G, Hartter S, Andersson K, Svensson JO, Widen J et al.
Inhibition of cytochrome P4502D6 activity with paroxetine normalizes
the ultrarapid metabolizer phenotype as measured by nortriptyline
pharmacokinetics and the debrisoquin test. Clin Pharmacol Ther 2001;
70: 327–335.
15 Spigset O, Granberg K, Hagg S, Norstrom A, Dahlqvist R. Relationship
between fluvoxamine pharmacokinetics and CYP2D6/CYP2C19 phe-
notype polymorphisms. Eur J Clin Pharmacol 1997; 52: 129–133.
16 Carrillo JA, Dahl ML, Svensson JO, Alm C, Rodriguez I, Bertilsson L.
Disposition of fluvoxamine in humans is determined by the poly-
morphic CYP2D6 and also by the CYP1A2 activity. Clin Pharmacol Ther
1996; 60: 183–190.
17 Spigset O, Granberg K, Hagg S, Soderstrom E, Dahlqvist R. Non-linear
fluvoxamine disposition. Br J Clin Pharmacol 1998; 45: 257–263.
18 Eap CB, Bondolfi G, Zullino D, Savary-Cosendai L, Powell-Golay K,
Kosel M et al. Concentrations of the enantiomers of fluoxetine and
norfluoxetine after multiple doses of fluoxetine in cytochrome
P4502D6 poor and extensive metabolizers. J Clin Psychopharmacol
2001; 21: 330–334.
19 Fuller RW, Snoddy HD, Krushinski JH, Robertson DW. Comparison of
norfluoxetine enantiomers as serotonin uptake inhibitors in vivo.
Neuropharmacology 1992; 31: 997–1000.
20 Sindrup SH, Brøsen K, Gram LF. Pharmacokinetics of the selective
serotonin reuptake inhibitor paroxetine: nonlinearity and relation to
the sparteine oxidation polymorphism. Clin Pharmacol Ther 1992; 1:
288–295.
21 Kirchheiner J, Henckel HB, Meineke I, Roots I, Brockmöller J. Impact of
the CYP2D6 ultra-rapid metabolizer genotype on mirtazapine phar-
macokinetics and adverse events in healthy volunteers. J Clin
Psychopharmacol 2004; 24: 647–652.
22 Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM.
Venlafaxine oxidation in vitro is catalysed by CYP2D6. Br J Clin
Pharmacol 1996; 41: 149–156.
23 Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K
et al. Effect of the CYP2D6*10 genotype on venlafaxine pharmaco-
kinetics in healthy adult volunteers. Br J Clin Pharmacol 1999; 47:
450–453.
24 Veefkind AH, Haffmans PM, Hoencamp E. Venlafaxine serum levels and
CYP2D6 genotype. Ther Drug Monit 2000; 22: 202–208.
25 Firkusny L, Gleiter CH. Maprotiline metabolism appears to co-
segregate with the genetically-determined CYP2D6 polymorphic
hydroxylation of debrisoquine. Br J Clin Pharmacol 1994; 37: 383–388.
26 Gabris G, Baumann P, Janzier-perey MPB, Woggon B, Küpfer A. N-
methylation of maprotiline in debrisoquine/mephenytoin-phenotyped
depressive patients. Biochemical Pharmacology 1985; 34: 409–410.
27 Faucette SR, Hawke RL, Lecluyse EL, Shord SS, Yan B, Laethem RM
et al. Validation of bupropion hydroxylation as a selective marker of
human cytochrome P450 2B6 catalytic activity. Drug Metab Dispos
2000; 28: 1222–1230.
28 Barbhaiya RH, Buch AB, Greene DS. Single and multiple dose
pharmacokinetics of nefazodone in subjects classified as extensive
and poor metabolizers of dextromethorphan. Br J Clin Pharmacol 1996;
42: 573–581.
29 Dostert P, Benedetti MS, Poggesi I. Review of the pharmacokinetics
and metabolism of reboxetine, a selective noradrenaline reuptake
Clinical role of polymorphisms in drug metabolism
13
inhibitor. Eur Neuropsychopharmacol 1997; 7(Suppl 1): S23–S35;
discussion S71–S73.
30 Schoerlin MP, Blouin RA, Pfefen JP, Guentert TW. Comparison of the
pharmacokinetics of moclobemide in poor and efficient metabolizers
of debrisoquine. Acta Psychiatr Scand Suppl 1990; 360: 98–100.
31 Härtter S, Dingemanse J, Baier D, Ziegler G, Hiemke C. The role of
cytochrome P450 2D6 in the metabolism of moclobemide. Eur
Neuropsychopharmacol 1996; 6: 225–230.
32 Gram LF, Guentert TW, Grange S, Vistisen K, Brøsen K. Moclobemide,
a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and
CYP1A2: a panel study. Clin Pharmacol Ther 1995; 57: 670–677.
33 Mihara K, Otani K, Suzuki A, Yasui N, Nakano H, Meng X et al.
Relationship between the CYP2D6 genotype and the steady-state
plasma concentrations of trazodone and its active metabolite m-
chlorophenylpiperazine. Psychopharmacology (Berl) 1997; 133: 95–98.
34 Rau T, Wohlleben G, Wuttke H, Thuerauf N, Lunkenheimer J, Lanczik
M et al. CYP2D6 genotype: impact on adverse effects and nonresponse
during treatment with antidepressants-a pilot study. Clin Pharmacol
Ther 2004; 75: 386–393.
35 Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A, Muller M,
Hiemke C et al. Impact of polymorphisms of cytochrome-P450
isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical
effects of antidepressants in a naturalistic clinical setting. Eur J Clin
Pharmacol 2004; 60: 329–336.
36 Lessard E, Yessine M, Hamelin B, O’Hara G, LeBlanc J, Turgeon J.
Influence of CYP2D6 activity on the disposition and cardiovascular
toxicity of the antidepressant agent venlafaxine in humans. Pharma-
cogenetics 1999; 9: 435–443.
37 Chen S, Chou WH, Blouin RA, Mao Z, Humphries LL, Meek QC et al.
The cytochrome P450 2D6 (CYP2D6) enzyme polymorphism: screen-
ing costs and influence on clinical outcomes in psychiatry. Clin
Pharmacol Ther 1996; 60: 522–534.
38 Kirchheiner J, Brosen K, Dahl ML, Gram LF, Kasper S, Roots I et al.
CYP2D6 and CYP2C19 genotype-based dose recommendations for
antidepressants: a first step towards subpopulation-specific dosages.
Acta Psychiatr Scand 2001; 104: 173–192.
39 Lennard MS, Silas JH, Freestone S, Trevethick J. Defective metabolism
of metoprolol in poor hydroxylators of debrisoquine. Br J Clin
Pharmacol 1982; 14: 301–303.
40 Lennard MS, Tucker GT, Silas JH, Freestone S, Ramsay LE, Woods HF.
Differential stereoselective metabolism of metoprolol in extensive
and poor debrisoquin metabolizers. Clin Pharmacol Ther 1983; 34:
732–737.
41 Koytchev R, Alken RG, Vlahov V, Kirkov V, Kaneva R, Thyroff Friesinger
U et al. Influence of the cytochrome P4502D6*4 allele on the
pharmacokinetics of controlled-release metoprolol. Eur J Clin Pharma-
col 1998; 54: 469–474.
42 McGourty JC, Silas JH, Lennard MS, Tucker GT, Woods HF. Metoprolol
metabolism and debrisoquine oxidation polymorphism–population
and family studies. Br J Clin Pharmacol 1985; 20: 555–566.
43 Lennard MS, Silas JH, Freestone S, Ramsay LE, Tucker GT, Woods HF.
Oxidation phenotype – a major determinant of metoprolol metabo-
lism and response. N Engl J Med 1982; 307: 1558–1560.
44 Kirchheiner J, Heesch C, Bauer S, Meisel C, Seringer A, Goldammer M
et al. Impact of the ultrarapid metabolizer genotype of cytochrome
P450 2D6 on metoprolol pharmacokinetics and pharmacodynamics.
Clin Pharmacol Ther 2004; 76: 302–312.
45 Neugebauer G, Akpan W, Kaufmann B, Reiff K. Stereoselective
disposition of carvedilol in man after intravenous and oral administra-
tion of the racemic compound. Eur J Clin Pharmacol 1990; 38:
108–111.
46 Oldham HG, Clarke SE. In vitro identification of the human
cytochrome P450 enzymes involved in the metabolism of R(+)- and
S()-carvedilol. Drug Metab Dispos 1997; 25: 970–977.
47 Zhou HH, Wood AJJ. Stereoselective disposition of carvedilol is
determined by CYP2D6. Clin Pharmacol Ther 1995; 57: 518–524.
48 Graff DW, Williamson KM, Pieper JA, Carson SW, Adams Jr KF, Cascio
WE et al. Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6
activity, and autonomic balance in heart failure patients. J Clin
Pharmacol 2001; 41: 97–106.
49 Kirchheiner J, Bauer S, Meineke I, Rohde W, Prang V, Meisel C et al.
Impact of CYP2C9 and CYP2C19 polymorphisms on tolbutamide
The Pharmacogenomics Journal
 Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
14
kinetics and the insulin and glucose response in healthy volunteers.
Pharmacogenetics 2002; 12: 101–109.
50 Stearns RA, Chakravarty PK, Chen R, Chiu SH. Biotransformation of
losartan to its active carboxylic acid metabolite in human liver
microsomes. Role of cytochrome P4502C and 3A subfamily members.
Drug Metab Dispos 1995; 23: 207–215.
51 McCrea JB, Cribb A, Rushmore T, Osborne B, Gillen L, Lo MW et al.
Phenotypic and genotypic investigations of a healthy volunteer
deficient in the conversion of losartan to its active metabolite E-31.
Clin Pharmacol Ther 1999; 65: 348–352.
52 Yasar U, Forslund-Bergengren C, Tybring G, Dorado P, Llerena A,
Sjoqvist F et al. Pharmacokinetics of losartan and its metabolite
E-3174 in relation to the CYP2C9 genotype. Clin Pharmacol Ther 2002;
71: 89–98.
53 Lee CR, Pieper JA, Frye RF, Hinderliter AL, Blaisdell JA, Goldstein JA.
Tolbutamide, flurbiprofen, and losartan as probes of CYP2C9 activity
in humans. J Clin Pharmacol 2003; 43: 84–91.
54 Hallberg P, Karlsson J, Kurland L, Lind L, Kahan T, Malmqvist K et al.
The CYP2C9 genotype predicts the blood pressure response to
irbesartan: results from the Swedish Irbesartan Left Ventricular
Hypertrophy Investigation vs Atenolol (S0ILVHIA) trial. J Hypertens
2002; 20: 2089–2093.
55 Uchida S, Watanabe H, Nishio S, Hashimoto H, Yamazaki K, Hayashi H
et al. Altered pharmacokinetics and excessive hypotensive effect of
candesartan in a patient with the CYP2C91/3 genotype. Clin
Pharmacol Ther 2003; 74: 505–508.
56 Adcock DM, Koftan C, Crisan D, Kiechle FL. Effect of polymorphisms in
the cytochrome P450 CYP2C9 gene on warfarin anticoagulation. Arch
Pathol Lab Med 2004; 128: 1360–1363.
57 Miners JO, Birkett DJ. Cytochrome P4502C9: an enzyme of major
importance in human drug metabolism. Br J Clin Pharmacol 1998; 45:
525–538.
58 Scordo MG, Pengo V, Spina E, Dahl ML, Gusella M, Padrini R. Influence
of CYP2C9 and CYP2C19 genetic polymorphisms on warfarin
maintenance dose and metabolic clearance. Clin Pharmacol Ther
2002; 72: 702–710.
59 Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanpra-
chanh SL, Farin FM et al. Association between CYP2C9 genetic variants
and anticoagulation-related outcomes during warfarin therapy. JAMA
2002; 287: 1690–1698.
60 Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms
in the cytochrome P450 CYP2C9 with warfarin dose requirement and
risk of bleeding complications. Lancet 1999; 353: 717–719.
61 Takahashi H, Wilkinson GR, Padrini R, Echizen H. CYP2C9 and oral
anticoagulation therapy with acenocoumarol and warfarin:similarities
yet differences. Clin Pharmacol Ther 2004; 75: 376–380.
62 Morin S, Bodin L, Loriot MA, Thijssen HH, Robert A, Strabach S et al.
Pharmacogenetics of acenocoumarol pharmacodynamics. Clin Phar-
macol Ther 2004; 75: 403–414.
63 Schalekamp T, van Geest-Daalderop JH, de Vries-Goldschmeding H,
Conemans J, Bernsen MjM, de Boer A. Acenocoumarol stabilization
is delayed in CYP2C93 carriers. Clin Pharmacol Ther 2004; 75:
394–402.
64 Visser LE, van Vliet M, van Schaik RH, Kasbergen AA, De Smet PA, Vulto
AG et al. The risk of overanticoagulation in patients with cytochrome
P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenpro-
coumon. Pharmacogenetics 2004; 14: 27–33.
65 Visser LE, van Schaik RH, van Vliet M, Trienekens PH, De Smet PA,
Vulto AG et al. The risk of bleeding complications in patients with
cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol
or phenprocoumon. Thromb Haemost 2004; 92: 61–66.
66 Kirchheiner J, Ufer M, Walter EC, Kammerer B, Kahlich R, Meisel C et al.
Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and
S-phenprocoumon in healthy volunteers. Pharmacogenetics 2004; 14:
19–26.
67 Hummers-Pradier E, Hess S, Adham IM, Papke T, Pieske B, Kochen
MM. Determination of bleeding risk using genetic markers in patients
taking phenprocoumon. Eur J Clin Pharmacol 2003; 59: 213–219.
68 Schalekamp T, Oosterhof M, van Meegen E, van Der Meer FJ,
Conemans J, Hermans M et al. Effects of cytochrome P450 2C9
polymorphisms on phenprocoumon anticoagulation status. Clin
Pharmacol Ther 2004; 76: 409–417.
The Pharmacogenomics Journal
69 Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP et al.
The impact of CYP2C9 and VKORC1 genetic polymorphism and patient
characteristics upon warfarin dose requirements: proposal for a new
dosing regimen. Blood 2005; 106: 2329–2333.
70 Schalekamp T, Brasse BP, Roijers JF, van Meegen E, van der Meer FJ,
van Wijk EM et al. VKORC1 and CYP2C9 genotypes and phenprocou-
mon anticoagulation status: interaction between both genotypes
affects dose requirement. Clin Pharmacol Ther 2007; 81: 185–193.
71 Montes R, Ruiz de Gaona E, Martinez-Gonzalez MA, Alberca I, Hermida
J. The c.1639G4A polymorphism of the VKORC1 gene is a major
determinant of the response to acenocoumarol in anticoagulated
patients. Br J Haematol 2006; 133: 183–187.
72 De Morais SM, Wilkinson GR, Blaisdell J, Meyer UA, Nakamura K,
Goldstein JA. Identification of a new genetic defect responsible for the
polymorphism of (S)-mephenytoin metabolism in Japanese. Mol
Pharmacol 1994; 46: 594–598.
73 Andersson T, Holmberg J, Rohss K, Walan A. Pharmacokinetics and
effect on caffeine metabolism of the proton pump inhibitors,
omeprazole, lansoprazole, and pantoprazole. Br J Clin Pharmacol
1998; 45: 369–375.
74 Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton
pump inhibitors. Basic Clin Pharmacol Toxicol 2004; 95: 2–8.
75 Chong E, Ensom MH. Pharmacogenetics of the proton pump
inhibitors: a systematic review. Pharmacotherapy 2003; 23: 460–471.
76 Fuhr U, Jetter A. Rabeprazole: pharmacokinetics and pharmacokinetic
drug interactions. Pharmazie 2002; 57: 595–601.
77 Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Nakagawa K et al.
Effects of genotypic differences in CYP2C19 status on cure rates for
Helicobacter pylori infection by dual therapy with rabeprazole plus
amoxicillin. Pharmacogenetics 2001; 11: 341–348.
78 Furuta T, Shirai N, Takashima M, Xiao F, Hanai H, Sugimura H et al.
Effect of genotypic differences in CYP2C19 on cure rates for
Helicobacter pylori infection by triple therapy with a proton pump
inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther 2001;
69: 158–168.
79 Furuta T, Ohashi K, Kamata T, Takashima M, Kosuge K, Kawasaki T
et al. Effect of genetic differences in omeprazole metabolism on cure
rates for Helicobacter pylori infection and peptic ulcer. Ann Intern Med
1998; 129: 1027–1030.
80 Furuta T, Shirai N, Sugimoto M, Ohashi K, Ishizaki T. Pharmacoge-
nomics of proton pump inhibitors. Pharmacogenomics 2004; 5:
181–202.
81 Wedlund PJ. The CYP2C19 enzyme polymorphism. Pharmacology
2000; 61: 174–183.
82 Schwab M, Schaeffeler E, Klotz U, Treiber G. CYP2C19 polymorphism
is a major predictor of treatment failure in white patients by use of
lansoprazole-based quadruple therapy for eradication of Helicobacter
pylori. Clin Pharmacol Ther 2004; 76: 201–209.
83 Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH. The effect of CYP2C19
polymorphisms on H. pylori eradication rate in dual and triple
first-line PPI therapies: a meta-analysis. Am J Gastroenterol 2006; 101:
1467–1475.
84 Oscarson M. Pharmacogenetics of drug metabolising enzymes:
importance for personalised medicine. Clin Chem Lab Med 2003; 41:
573–580.
85 Collie-Duguid ES, Pritchard SC, Powrie RH, Sludden J, Collier DA, Li T
et al. The frequency and distribution of thiopurine methyltransferase
alleles in Caucasian and Asian populations. Pharmacogenetics 1999; 9:
37–42.
86 Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics:
monogenic inheritance of erythrocyte thiopurine methyltransferase
activity. Am J Hum Genet 1980; 32: 651–662.
87 Evans WE, Hon YY, Bomgaars L, Coutre S, Holdsworth M, Janco R et al.
Preponderance of thiopurine S-methyltransferase deficiency and
heterozygosity among patients intolerant to mercaptopurine or
azathioprine. J Clin Oncol 2001; 19: 2293–2301.
88 Lennard L, Van Loon JA, Lilleyman JS, Weinshilboum RM. Thiopurine
pharmacogenetics in leukemia: correlation of erythrocyte thiopurine
methyltransferase activity and 6-thioguanine nucleotide concentra-
tions. Clin Pharmacol Ther 1987; 41: 18–25.
89 McLeod HL, Coulthard S, Thomas AE, Pritchard SC, King DJ, Richards
SM et al. Analysis of thiopurine methyltransferase variant alleles in

childhood acute lymphoblastic leukaemia. Br J Haematol 1999; 105:
696–700.
90 Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH et al.
Molecular diagnosis of thiopurine S-methyltransferase deficiency:
genetic basis for azathioprine and mercaptopurine intolerance. Ann
Intern Med 1997; 126: 608–614.
91 Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced
myelosuppression in thiopurine methyltransferase deficient heart
transplant recipient. Lancet 1993; 341: 436.
92 Nagasubramanian R, Innocenti F, Ratain MJ. Pharmacogenetics in
cancer treatment. Annu Rev Med 2003; 54: 437–452.
93 Colombel JF, Ferrari N, Debuysere H, Marteau P, Gendre JP, Bonaz B
et al. Genotypic analysis of thiopurine S-methyltransferase in patients
with Crohn’s disease and severe myelosuppression during azathioprine
therapy. Gastroenterology 2000; 118: 1025–1030.
94 Kroplin T, Weyer N, Gutsche S, Iven H. Thiopurine S-methyltransferase
activity in human erythrocytes: a new HPLC method using 6-
thioguanine as substrate. Eur J Clin Pharmacol 1998; 54: 265–271.
95 Schwab M, Schaeffeler E, Marx C, Zanger U, Aulitzky W, Eichelbaum
M. Shortcoming in the diagnosis of TPMT deficiency in a patient with
Crohn’s disease using phenotyping only. Gastroenterology 2001; 121:
498–499.
96 Lennard L. Therapeutic drug monitoring of antimetabolic cytotoxic
drugs. Br J Clin Pharmacol 1999; 47: 131–143.
97 Pazmino PA, Sladek SL, Weinshilboum RM. Thiol S-methylation in
uremia: erythrocyte enzyme activities and plasma inhibitors. Clin
Pharmacol Ther 1980; 28: 356–367.
98 Andersen JB, Szumlanski C, Weinshilboum RM, Schmiegelow K.
Pharmacokinetics, dose adjustments, and 6-mercaptopurine/metho-
trexate drug interactions in two patients with thiopurine methyltrans-
ferase deficiency. Acta Paediatr 1998; 87: 108–111.
99 Evans WE. Pharmacogenetics of thiopurine S-methyltransferase and
thiopurine therapy. Ther Drug Monit 2004; 26: 186–191.
100 Milan G, Etienne MC. 5-Fluorouracil. In: Grochow LB, Ames MM
(Hrsg) (eds.). A Clinical Guide to Chemotherapy Pharmacokinetics and
Pharmacodynamics. Williams & Wilkins: Baltimore, 1999 pp 289–300.
101 Gonzalez FJ, Fernandez-Salguero P. Diagnostic analysis, clinical
importance and molecular basis of dihydropyrimidine dehydrogenase
deficiency. Trends Pharmacol Sci 1995; 16: 325–327.
102 Wei X, McLeod HL, McMurrough J, Gonzalez FJ, Fernandez-Salguero
P. Molecular basis of the human dihydropyrimidine dehydrogenase
deficiency and 5-fluorouracil toxicity. J Clin Invest 1996; 98: 610–615.
103 Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of
cancer treatment. Cancer 1981; 47: 207–214.
104 Frickhofen N, Beck FJ, Jung B, Fuhr HG, Andrasch H, Sigmund M.
Capecitabine can induce acute coronary syndrome similar to
5-fluorouracil. Ann Oncol 2002; 13: 797–801.
105 Collie-Duguid ES, Etienne MC, Milano G, McLeod HL. Known variant
DPYD alleles do not explain DPD deficiency in cancer patients.
Pharmacogenetics 2000; 10: 217–223.
106 Fleming RA, Milano G, Thyss A, Etienne MC, Renee N, Schneider M
et al. Correlation between dihydropyrimidine dehydrogenase activity
in peripheral mononuclear cells and systemic clearance of fluorouracil
in cancer patients. Cancer Res 1992; 52: 2899–2902.
107 Van Kuilenburg AB, Van Lenthe H, Tromp A, Veltman PC, Van Gennip
AH. Pitfalls in the diagnosis of patients with a partial dihydropyrimidine
dehydrogenase deficiency. Clin Chem 2000; 46: 9–17.
108 Raida M, Schwabe W, Hausler P, Van Kuilenburg AB, Van Gennip AH,
Behnke D et al. Prevalence of a common point mutation in the
dihydropyrimidine dehydrogenase (DPD) gene within the 50 -splice
donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)-
related toxicity compared with controls. Clin Cancer Res 2001; 7:
2832–2839.
109 Van Kuilenburg AB, Baars JW, Meinsma R, Van Gennip AH. Lethal 5-
fluorouracil toxicity associated with a novel mutation in the
dihydropyrimidine dehydrogenase gene. Ann Oncol 2003; 14:
341–342.
110 Kollmannsberger C, Bokemeyer C, Marx C, Fischer J, Honecker F,
Schwab M et al. The association between mutations in the
dihydropyrimidine dehydrogenase gene and severe toxicity of the
treatment with s-fluorouracil: a prospective multicenter study.
Onkologie 2001; 25(Suppl. 6): 101.
Clinical role of polymorphisms in drug metabolism
D Tomalik-Scharte et al
15
111 van Kuilenburg AB, Haasjes J, Richel DJ, Zoetekouw L, Van Lenthe H,
De Abreu RA et al. Clinical implications of dihydropyrimidine
dehydrogenase (DPD) deficiency in patients with severe 5-fluoro-
uracil-associated toxicity: identification of new mutations in the DPD
gene. Clin Cancer Res 2000; 6: 4705–4712.
112 Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H et al. UGT1A1
haplotypes associated with reduced glucuronidation and increased
serum bilirubin in irinotecan-administered Japanese patients with
cancer. Clin Pharmacol Ther 2004; 75: 501–515.
113 Innocenti F, Iyer L, Ratain MJ. Pharmacogenetics of anticancer agents:
lessons from amonafide and irinotecan. Drug Metab Dispos 2001; 29:
596–600.
114 Araki K, Fujita K, Ando Y, Nagashima F, Yamamoto W, Endo H et al.
Pharmacogenetic impact of polymorphisms in the coding region of
the UGT1A1 gene on SN-38 glucuronidation in Japanese patients with
cancer. Cancer Sci 2006; 97: 1255–1259.
115 Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M et al.
Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict
the risk of severe neutropenia of irinotecan. J Clin Oncol 2004; 22:
1382–1388.
116 Ando Y, Saka H, Ando M, Sawa T, Muro K, Ueoka H et al.
Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan
toxicity: a pharmacogenetic analysis. Cancer Res 2000; 60:
6921–6926.
117 Maitland ML, Vasisht K, Ratain MJ. TPMT, UGT1A1 and DPYD:
genotyping to ensure safer cancer therapy? Trends Pharmacol Sci 2006;
27: 432–437.
118 Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility
risk factor for antituberculosis drug-induced hepatitis. Hepatology
2002; 35: 883–889.
119 Brockton N, Little J, Sharp L, Cotton SC. N-acetyltransferase
polymorphisms and colorectal cancer: a HuGE review. Am J Epidemiol
2000; 151: 846–861.
120 Garte S, Gaspari L, Alexandrie AK, Ambrosone C, Autrup H,
Autrup JL et al. Metabolic gene polymorphism frequencies in
control populations. Cancer Epidemiol Biomarkers Prev 2001; 10:
1239–1248.
121 Grant DM, Goodfellow GH, Sugamori KS, Durette K. Pharmacogentics
of the human arylamine N-actyltransferases. Pharmacology 2000; 61:
204–211.
122 Tiitinen H et al. Comparison of the isoniazid in activation in Finns and
Lapps. Ann Med Int Finn 1968; 57: 161.
123 Parkin DP, Vandenplas S, Botha FJ, Vandenplas ML, Seifart HI, van
Helden PD et al. Trimodality of isoniazid elimination: phenotype and
genotype in patients with tuberculosis. Am J Respir Crit Care Med 1997;
155: 1717–1722.
124 Kita T, Tanigawara Y, Chikazawa S, Hatanaka H, Sakaeda T, Komada F
et al. N-Acetyltransferase 2 genotype correlated with isoniazid
acetylation in Japanese tuberculous patients. Biol Pharm Bull 2001;
24: 544–549.
125 Kinzig-Schippers M, Tomalik-Scharte D, Jetter A, Scheidel B, Jakob V,
Rodamer M et al. Should we use N-acetyltransferase type 2
genotyping to personalize isoniazid doses? Antimicrob Agents Che-
mother 2005; 49: 1733–1738.
126 Clark DWJ. Genetically determine variability in acetylation and
oxidation: therapeutic implications. Drugs 1985; 29: 342–375.
127 Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R
et al. Slow N-acetyltransferase 2 genotype affects the incidence of
isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis
2000; 4: 256–261.
128 Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY et al.
Polymorphism of the N-acetyltransferase 2 gene as a susceptibility
risk factor for antituberculosis drug-induced hepatitis. Hepatology
2002; 35: 883–889.
129 Donald PR, Sirgel FA, Venter A, Parkin DP, Seifart HI, van de Wal BW
et al. The influence of human N-acetyltransferase genotype on
the early bactericidal activity of isoniazid. Clin Infect Dis 2004; 39:
1425–1430.
130 Kalow W. Pharmacogenetics and pharmacogenomics: origin, status,
and the hope for personalized medicine. Pharmacogenomics J 2006; 6:
162–165.
The Pharmacogenomics Journal