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See ARTICLE page 234

CYP2D6 Phenotype Prediction


From Genotype: Which System Is
the Best?
J Kirchheiner1
Genotyping of the polymorphic cytochrome P450 (CYP) 2D6
gene is used increasingly in clinical practice. Several psychiatric
hospitals already use CYP2D6 testing before treating a patient
with antidepressant or antipsychotic drug therapy. In other fields
of drug therapy, such as for breast cancer, CYP2D6 status has been
reported to be an independent predictor for the outcome with
tamoxifen.1,2 Thus, a more favorable tamoxifen treatment seems to
be feasible through a priori genetic assessment of CYP2D6.
Several companies as well as academic
research institutions oer CYP2D6 genotyping, varying in types of alleles tested,
analytical methods, and costs of genotyping. However, the result of a CYP2D6
genetic test is not easy to interpret, given
that more than 70 alleles have been
dened that predict no, decreased, normal, or increased activity of the CYP2D6
enzyme. CYP2D6 alleles are assigned on
the basis of the appropriate key mutations,3 and the base numbering and allele
designation are published on the CYP
allele nomenclature website (http://www.
cypalleles.ki.se). Of particular interest in
clinical practice as well as in drug development is whether a patients individual
phenotype can be predicted from the

genotype. It is important to identify individuals at a specic risk for having undesired drug eects or therapeutic failure
due to low or high CYP2D6 activity and,
thus, to eventually apply a dose adjustment or change of therapeutic strategy.
The correct prediction of the phenotype,
however, has always been a matter of
discussion, and dierent nomenclature
systems for CYP2D6 activity have been
proposed, creating a confusing picture
for those who are not familiar with the
CYP2D6 issue.
The rst system proposed was based
on CYP2D6 phenotype, and it distinguished mainly between poor and
extensive metabolizers (PMs and
EMs, respectively). 4,5 The CYP2D6

1Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.

Correspondence: J Kirchheiner (julia.kirchheiner@uni-ulm.de)


doi:10.1038/sj.clpt.6100455

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 83 NUMBER 2 | FEBRUARY 2008

225

PERSPEC TIVES
phenotype, determined as the urinary
metabolic ratio of a suitable probe drug
such as sparteine or debrisoquine, typically shows a bimodal or trimodal distribution among European populations,
with the PMs representing 5% to 10%.
In their extensive genotypephenotype
comparison in a German (exclusively
Caucasian, ethnically) population,
Sachse et al. showed that 97% of all PMs
can be explained by the four decientactivity CYP2D6 alleles (*3, *4, *5, *6).6
However, whereas homozygous carriers
of the CYP2D6 alleles predicting decient enzyme activity clearly belong to
the PM phenotype, heterozygous carriers show a large variability in CYP2D6
phenotype, and other alleles causing decreased or increased CYP2D6
activity made it even more dicult to
correctly predict an individuals CYP2D6
phenotype.7 Many studies classied the
heterozygous carriers of the decient
CYP2D6-activity alleles as intermediate
metabolizers (IMs).6,8 However, considerable variability exists, depending
on the activity of the second, not inactive allele. Raimundo et al. addressed
the genetic base of the IM phenotype
and showed a polymorphism within the
promoter region that causes intermediate CYP2D6 activity.9
In Asiatic countries, alleles with absent
CYP2D6 activity are very rare, but the
*10 allele causing decreased but not
absent CYP2D6 activity occurs quite
frequently, leading to a classification
into heterozygous and homozygous
carriers corresponding to a phenotype
system with high, intermediate, and low
CYP2D6 activity.1014
To account for the eect of the single
CYP2D6 alleles, Steimer et al. derived
the system of the so-called semiquantitative CYP2D6 gene dose from
antidepressant drug plasma concentration data. 15 The CYP2D6 genotype is
expressed as the sum of the gene dose
for both alleles, with 1 for functional
alleles, 0 for completely dysfunctional
alleles, and 0.5 for alleles with decreased
activity. For example, an individual with
a CYP2D6 gene duplication would carry
the semiquantitative gene dose of 3.
This system was also applied for other
CYP2D6 substrates and was shown to be
226

more accurate in prediction of CYP2D6


in vivo activity than the traditional PMIM-EM system.1518
In 2003, Roche launched the first
test cleared by the US Food and Drug
Administration for analysis of CYP2D6
(and CYP2C19)the AmpliChip
CYP450 Testand introduced a different genotypephenotype correlation
for the PM, IM, EM, and ultrarapidmetabolizer (UM) phenotype system. The
tests product monograph categorized
the heterozygous carriers of decient
alleles in combination with high-activity
alleles as EMs and allele combinations of
two decreased (or absent)-activity alleles as IMs. Thus, the history of dierent
genotype-phenotype systems for CYP2D6
is quite confusing, and the need emerges
for a consensus on one best-suited
genotype-phenotype system.
In this issue, Gaedigk et al. propose
a new system based on the presumed
activity of individual CYP2D6 alleles.19
This tool reduces the complex data of
95 genotypes into four activity-score
groups per allele. This is an interesting
and very useful approach, especially in
that the authors base their calculations
on a very large data set of phenotyped
patients. The phenotype scores have
been derived from urinary ratios of
dextromethorphan, a frequent probe
drug for CYP2D6 phenotyping. However,
dextromethorphan urinary ratios have
some limitations for estimating in vivo
enzyme activity, because no linear
correlation exists between enzyme activity
and urinary ratios. In addition, urinary
ratios are pH dependent; also, they
depend on renal and hepatic transport.
Thus, even if numeric, the phenotype
score should not lead clinicians to adjust
the dosages of drugs that are CYP2D6
substrates. Dose adjustments must still
be based on dierences in oral clearance
of the respective drugs.
In the case of the dextromethorphan
urinary metabolic ratio, according to the
data presented by Gaedigk et al.,19 about
60% of the variability was explained by
the CYP2D6 genotype. Still, the remaining variability is substantial and probably similar to that for activity metrics
of enzymes with less prominent genetic
polymorphisms.20 This might be attrib-

utable to dextromethorphans capacity to


distinguish between PMs and EMs, but it
is poor at distinguishing between rapid
and ultrarapid metabolizers because urinary excretion of the parent drug is low
in both groups. In addition, dextromethorphan is a substrate of the highly
inducible and genetically polymorphic
CYP3A enzymes 4 and 5. For broader
clinical application, it would be desirable
to account for additional sources of variability in CYP2D6 activity.
In addition to the activity-score system,
the authors calculate the probability
that a subject with a given genotype will
present within a certain phenotype using
the traditional classication (UM, EM,
IM, and PM). To validate the system,
large pooled data sets of phenotyped and
genotyped healthy volunteers of dierent
ethnicities and ages were used. The
authors emphasize that the probability
of belonging to a particular phenotype
group might be over- or underestimated
when the prediction is based on an
ethnically mixed population. This leads
to another issue that generally hampers
individual phenotype prediction: genetic
admixture. Thus, despite the need for
accurate phenotype prediction from
CYP2D6 genotype results, there is only
a small probability that phenotype will
be correctly predicted for a given individual, regardless of the system used.
It might be that the traditional classication into UMs, EMs, IMs, and PMs
that has been internationally used and
validated in recent years will be surpassed by a new quantitative system
accounting more precisely for the individual allelic activity. Future tasks will
include not only predicting CYP2D6
activity in vivo but also transforming
this information into guidelines for
an individual patient. Treatment algorithms must be developed for carriers
of dierent CYP2D6 allelesfor drugs
that are inactivated as well as for drugs
that are bioactivated by CYP2D6, such as
codeine, tramadol, encainide, and, most
importantly, tamoxifen. Particularly in
tamoxifen therapy of breast cancer, this
approach becomes critical for duration
of survival, which is much more important than costs and days of hospitalization or quality of life.

VOLUME 83 NUMBER 2 | FEBRUARY 2008 | www.nature.com/cpt

PERSPEC TIVES
CONFLICT OF INTEREST
The author declared no conflict of interest.
2008 ASCPT

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genotype on venlafaxine pharmacokinetics in
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metabolizer genotype of cytochrome P450


2D6 on metoprolol pharmacokinetics and
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17. Kirchheiner, J. et al. Pharmacokinetics of
codeine and its metabolite morphine in ultrarapid metabolizers due to CYP2D6 duplication.
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18. Brockmller, J., Kirchheiner, J., Meisel, C. &
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drug development and in drug treatment.


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The State of Innovation in Drug


Development
I Kola1
The pharmaceutical industry is facing tremendous pressure, not
only from payers but as a result of public perception, regulatory
hurdles, and the intricacies of research and development (R&D).
The latter two are significant in that they affect the number of
drugs that may be registered by regulatory authorities, the time
to discover and develop drugs, and the cost of drug development.
Because drug development has been stagnant in terms of
innovation, there exists huge potential for innovation. Failure
to innovate drug development will render the big pharma
model unsustainable.

The past several years have seen the lowest


number of drugs approved in the industrys history.1 Additionally, the fully loaded
cost to discover and develop a drug is the
highest it has ever been and is increasing
exponentially (some estimates place this
cost at approximately US$1.7 billion2).
The time to discover and develop drugs is
also increasing signicantly. This is exacerbated by regulatory authorities demands
for more data in the post-Vioxx era. All
of these signicantly compound the R&D
productivity pressure on the industry, fostering a vicious circle.
Interestingly, however, the pressures of
R&D may serve as a profound catalyst
for transforming the process and in
the long term lead to innovation in
drug discovery and development. The

drug discovery process has enjoyed


some significant advancesamong
others, diversication of the chemical
compound collections, high-throughput
screening for targets, important tools
for target identication and validation,
the use of human genetics and genetic
animal models, the sequencing of the
entire human genome as well as that of
several other species, and technologies
such as transcriptional profiling and
RNA-me diated interference. On
the other hand, the process of drug
development has been relatively stagnant,
so much so that the US Food and Drug
Administration has been proactive and
issued a paper3 calling for the industry
to innovate the development process.
Innovations in drug development

1Schering Plough Corporation, Kenilworth, New Jersey, USA. Correspondence: I Kola (ismail.kola@spcorp.
com)

doi:10.1038/sj.clpt.6100479

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