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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.
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
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PERSPEC TIVES
CONFLICT OF INTEREST
The author declared no conflict of interest.
2008 ASCPT
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1Schering Plough Corporation, Kenilworth, New Jersey, USA. Correspondence: I Kola (ismail.kola@spcorp.
com)
doi:10.1038/sj.clpt.6100479
227