Indian Journal of Pharmacology 2001; 33: 147-169 EDUCATIONAL FORUM
Correspondence: C. Adithan
GENETIC POLYMORPHISM OF CYP2D6
*BENNY K. ABRAHAM, C. ADITHAN
Clinical Pharmacology Unit, Department of Pharmacology, Jawaharlal Institute of
Postgraduate Medical Education and Research, Pondicherry-605 006.
*Present address: Department of Pharmaceutical Sciences, M.G. University,
Cheruvandoor campus, Ettumanoor (P.O.)-686 631. Kerala
Manuscript Received: 19.9.2000Accepted: 19.2.2001
CYP2D6 is polymorphically distributed and is responsible for the metabolism of several clinically important
drugs. It is also related to several pathophysiological conditions. Defect alleles, causing poor metaboliser
(PM) phenotype and alleles with duplicated or multiduplicated active genes, causing ultra extensive
metabolism (UEM) have been described. CYP2D6 polymorphism exhibits pronounced interethnic variation.
While initial observation and studies focused on population of Caucasian origin, later other populations
also studied extensively. Differences in metabolism of drugs can lead to severe toxicity or therapeutic
failure by altering the relation between dose and blood concentration of pharmacologically active drug or
metabolite. Knowledge of individual’s CYP2D6 status may be clinically and economically important and
could provide the basis for a rational approach to drug prescription.
‘CYP’ is the abbreviation for cytochrome P-450, a
subgroup of related enzymes or isoenzymes located
in the endoplasmic reticulum and expressed mainly
in the liver. It is also present in other organs, such as
the intestine and the brain4. In mammals, most
xenobiotics are metabolised via hepatic phase 1
metabolism by means of CYP monooxygenases5.
Thirty or more different forms of these haem thiolate
proteins have been characterized in humans3. The
P450 superfamily is composed of families and sub-
families of enzyme that are defined solely on the basis
of their amino acid sequence similarities. With few
exceptions, a P450 protein sequence from one fam-
ily exhibits upto 40% resemblance to a P450 from
other family. P450s with in a single subfamily always
share greater than 55% sequence similarity6,7.
Evolution of CYP2D6 polymorphism
Between 1975 and 1977 two groups independently
discovered the genetic deficiency of debrisoqine8 and
Genetic polymorphism is defined as the inheritance of
a trait controlled by a single genetic locus with two alle-
les, in which the least common allele has a frequency
of about 1% or greater1. One of the most extensively
studied genetic polymorphisms known to influence drug
metabolism and response is the debrisoquine type
(CYP2D6) oxidation polymorphism. The discovery of
CYP2D6 polymorphism created new interest in the role
of pharmacogenetics in clinical pharmacology2.
Genetic polymorphism has been linked to three
classes of phenotypes based on the extent of drug
metabolism. Extensive metabolism (EM) of a drug is
characteristic of the normal population; poor metabo-
lism (PM) is associated with accumulation of spe-
cific drug substrates and is typically an autosomal
recessive trait requiring mutation and/or deletion of
both alleles for phenotypic expression; and ultra ex-
tensive metabolism (UEM) results in increased drug
metabolism and is an autosomal dominant trait aris-
ing from gene amplification3.
BENNY K. ABRAHAM AND C. ADITHAN
sparteine9 metabolism. The discovery of genetic poly-
morphism in the metabolism of the two prototype
drugs was not the result of a planned strategy but
rather an incidental observation. A dramatic event in
a pharmacokinetic study prompted the initial search
for a specific metabolic defect: the investigator, Dr.
Smith, who was participating in a study on debriso-
quine, a sympatholytic antihypertensive drug, had a
much more pronounced hypotensive response than
his colleagues, collapsing from a sub therapeutic
dose. This was found to be due to impaired 4-
hydroxylation of debrisoquine8.
Similarly in 1975, during the course of kinetic stud-
ies by Eichelbaun et al with a slow release prepara-
tion of sparteine, two subjects developed side effects
such as diplopia, blurred vision, dizziness and head-
ache. When analysing the plasma levels of sparteine
in those subjects the reason for the development of
side effects become evident. Compared to all the
other subjects studied, their plasma levels were 3 to
4 times higher, although the same dose had been
given to every subject9.
Family and population studies10 uncovered a genetic
polymorphism and later work established that the two
independently discovered defects in drug oxidation
co-segregated in Caucasians (PM for sparteine ex-
hibit impaired debrisoquine metabolism and vice
versa) and the term sparteine/debrisoquine
polymorphism was coined11. However there are ap-
parent exemptions to this rule. For instance, in a study
in Ghana, the ability of Ghanaians to oxidise sparteine
was independent of their capacity for debrisoquine
Guidelines on nomenclature for individual cytochrome
P450 isoform have been internationally agreed upon
and are regularly updated. Genes encoding the P450
enzyme are designated as CYP. Because of the di-
versity of the cytochrome family, a nomenclature sys-
tem based on sequence identity has been developed
to assist in unifying scientific efforts in this area and
to provide a basis for nomenclature of newly recog-
nized members of this gene superfamily. For exam-
ple, CYP2D6 is isoform 6 of subfamily D included in
the 2 CYP family3.
In the past, CYP2D6 alleles have been named arbi-
trarily using a single letter after the gene name,7 but
with increasing numbers of alleles being detected,
this system is now inadequate. The general recom-
mendation is that the gene and allele are separated
by an asterisk. Specific alleles are named by Arabic
numerals or a combination of Arabic numerals followed
by a capitalized Latin letter. There are no spaces be-
tween gene, asterisk and allele and the entire gene-
allele symbol is italicized (e.g. CYP2D6*1A) 13,14.
Since a number of CYP2D6 alleles share common
key mutations but differ with respect to other base
changes, these should be given the same Arabic
number (denoting their allele group) and distinguished
by capitalized Latin letters (denoting the allele sub
groups). For example, both CYP2D6*4A and
CYP2D6*4B have the same mutation but differ by a
single silent base substitution13.
Extra copies of an allele (duplicated or amplified) may
exist in tandem; for example, the CYP2D6L2 allele
contains two copies of CYP2D6L. Here the entire
arrangement of alleles should be referred to as
CYP2D6*2X2. When duplication is not with the same
subgroup, they are separated with a coma (e.g.
A non-italicized form of the allele is used to name
the protein with asterisk omitted and replaced by a
single spacing e.g.: CYP2D6 1. Both alleles italicized
and separated by slash to name the genotype des-
For a review of the most recent nomenclature of
CYP2D6, refer to Daly et al 13 and Garte and Crosti14.
This nomenclature system is also used for other P450
alleles like CYP2A6*1, CYP2C9*2, CYP2C19*2 etc.
Descriptions of the alleles as well as the nomencla-
ture and relevant references are continuously up-
dated at the new web page (http://www.imm.ki.se/
The CYP2D6 gene resides in the CYP2D6-8 clus-
ters on chromosome 22 in association with the
CYP2D7P and CYP2D8P pseudogenes15. Defective
alleles can be the result of gene deletion16, gene con-
versions with related pseudogenes and single base
mutations17 causing frameshift, missense, nonsense
or splice-site mutations18,19. The homozygous pres-
ence of such alleles leads to a total absence of ac-
tive enzyme and an impaired ability to metabolise
Table 1. Inhibitors of CYP2D6.
probe drugs specific for the drug-metabolizing en-
zyme. These subjects are classified as PM16-20.
In addition to defective CYP genes, there are also
alleles that cause diminished or altered drug metabo-
lism. This results in enzyme products that exhibit
impaired folding capacity and therefore the expres-
sion of the functional enzyme is severely dimin-
ished17,18. Among extensive metabolisers, heterozy-
gotes (one functional gene) have higher medium
metabolic efficacy than those who are homozygous
for the wild-type allele (two functional genes), but with
Another type of metabolism is known as ultra rapid
metabolism and is caused by occurrence of dupli-
cated, multiduplicated or amplified CYP2D6 genes.
At present, alleles with two, three, four, five and 13
gene copies in tandem have been reported and the
number of individuals carrying multiple CYP2D6 gene
copies is highest in Ethiopia and Saudi Arabia, where
upto one third of the population displays this pheno-
type18. In a Swedish family, a father, a daughter and
a son were shown to have 12 copies of a functional
CYP2D6L gene with one normal gene and showed
extremely high CYP2D6 activity24.
Although clear criteria have not been formed to struc-
turally assess whether a compound is metabolized
by this enzyme, it is observed that most of CYP2D6
metabolized substrates and inhibitors have a basic
nitrogen and are oxidized at a site within 0.5-0.7nm
of this basic nitrogen. It may also have a flat lipophilic
region and functional groups which have capacity for
electrostatic interactions or the ability to form hydro-
gen bonds25,26. The enzyme even shows stereose-
lectivity also. In extensive metabolizers, inactive
R-metoprolol is metabolized faster than the active
S-enantiomer whereas this metabolism is not
sterioselective in poor metabolisers27. Isoform selec-
tivity of CYP2D6 is observed in mianserin metabo-
INHIBITION AND INDUCTION OF CYP2D6
Quinidine is the most potent inhibitor (ki=0.03) of
CYP2D6 26. Quinine, which is a diastereoisomer of
quinidine, is several hundred times less potent in-
hibitor than quinidine. However, quinidine is not a
substrate of CYP2D6 1. Single oral dose of 200 mg
quinidine sulphate is adequate to convert most ex-
tensive metabolisers to poor metabolisers29. Fluox-
etine30-32, paroxetine32 and propofenone33 are also po-
tent inhibitors of CYP2D6 with inhibition constant in
the low nanomolar range. A list of inhibitors of
CYP2D6 is given in Table 1.
Unlike many members of the CYP enzyme family, the
CYP2D6 enzyme is not affected by classic enzyme in-
ducers such as phenobarbitone34. Rifampicin treatment
has given only a 30% increase in clearance of sparteine,
but metabolic ratio was not significantly changed34.
About 33% reduction in the metabolic ratio of debriso-
quine has been observed in female EM using
BENNY K. ABRAHAM AND C. ADITHAN
contraceptives35. During the menstrual cycle, insig-
nificant decrease in debrisoquine metabolic ratio was
observed during the luteal phase compared to preo-
vulatory phase36, 37. Heavy cigarette smoking and
ovariectomy induced this enzyme activity but only to
a minor extent1. In contrast, there is evidence that
pregnancy has a profound influence on CYP2D6 ac-
tivity. Marked increase in metabolism of metoprolol38
and dextromethorphan36 has been reported during
ASSESSMENT OF INDIVIDUAL CYP2D6 ACTIVITY
The activity of CYP2D6 enzyme can be assessed
by means of phenotyping or genotyping3.
Phenotyping requires intake of a probe drug; the me-
tabolism of which is known to be solely dependent
on CYP2D6 enzyme. The excretion of parent com-
pound and/or metabolite in urine allows to calculate
the metabolic ratio, which is a measure of individual
CYP2D6 activity3, 11.
In a typical phenotyping experiment, individuals were
administered an oral dose of the probe drug usually
at a subtherapeutic level, and urine was collected over
a period of 8-12 hours. Total yield of parent compound
and metabolites were determined and the metabolite/
parent compound ratio, termed metabolic ratio (MR)
was plotted as frequency distribution histogram. A
polymorphism is indicated by bimodal frequency dis-
tribution curve with the antimode between the two
populations. Antimode which separates the exten-
sive metabolisers from poor metabolisers serves as a
baseline to distinguish these two groups20. A probit
plot39 or normal test variable (NTV) plot40 also can be
used to express the bimodal distribution.
Different probe drugs are used for CYP2D6 pheno-
typing. Earlier phenotyping studies have been per-
formed with debrisoquine and sparteine. Later
dextromethorphan41, metoprolol42 and codeine43 were
also used for phenotyping CYP2D6 activity.
The antimodes of this bimodal distribution in Cauca-
sians are about 20, 0.3 and 12.6 for sparteine3,
dextromethorphan3, 41 and debrisoquine3, 41/metopro-
lol42 respectively. The metabolic ratio is a function of
factors such as renal drug clearance as well as en-
zyme activity. Environmental factors may modify these
variables, which may give rise to differences in the
antimode of the MR between ethnic groups44.
Dextromethorphan represents the only probe drug
readily available as OTC drug in most of the coun-
tries11. It is also considered safe for children and preg-
nant women33. However metabolism of this drug pro-
ceeds simultaneously via other enzymes such as
CYP3A4 and results should therefore be interpreted
with some caution11. Blood5 and salivary45, 46 analy-
sis also have been used for phenotyping studies.
Phenotyping has several drawbacks. It is hampered
by a complicated protocol of testing, risks of adverse
drug reactions, problem with incorrect phenotype
assignment due to co-administration of drugs and
confounding effect of disease3. This approach may
be hampered in patients who concomitantly receive
drugs that are metabolized by CYP2D6 and/or in-
hibit this enzyme. As a consequence metabolite for-
mation of the probe drug may be reduced despite a
normal enzyme activity and the metabolic ratio in
urine would indicate a poor metaboliser. Such ap-
parent transformation of an EM-phenotype to a PM-
phenotype is termed as phenocopying11, 47.
However, phenotyping is the only approach to evalu-
ate enzyme function. If post-translational variation
contributes to the individual CYP2D6 activity then
phenotyping will be the only way to identify such phe-
nomena11. Phenotyping is useful in revealing drug-
drug interactions or defect in overall process of drug
Genotyping involves identification of defined genetic
mutation that give rise to the specific drug metabo-
lism phenotype. These mutations include genetic al-
terations that lead to overexpression (gene amplifi-
cation), absence of an active protein product (null
allele), or production of a mutant protein with dimin-
ished catalytic capacity (inactivating allele) 3.
DNA isolated from peripheral lymphocytes can be
used for genotyping. Two commonly used methods
in genotyping are PCR-RFLP method and allele-spe-
cific PCR3. In the former technique, specific region
of the gene of interest is amplified by PCR followed
by digestion of the amplified DNA product with re-
striction endonucleases. The size of the digestion
products is easily evaluated by agarose gel electro-
phoresis with ethidium bromide staining and UV
Table 2. CYP2D6 alleles§
AlleleChanges Xba 1Trivial nameEffect Enzyme activity
CYP2D6*1ANone 29Wild-typeNormal Normal
CYP2D6*1B3828G>A 29 Normal (d,s)
CYP2D6*1C1978C>T M4Normal (s)
CYP2D6*1XN 42N active
29 CYP2D6L R296C;
Decrease (dx, d)Decrease
BENNY K. ABRAHAM AND C. ADITHAN
(N=2, 3, 4, 5 or 13)
CYP2D6*3A2549A>del 29 CYP2D6A FrameshiftNone (d, s) None (b)
None (d, s)
None (d, s)None (b)
29 CYP2D6B P34S;
None (d, s)None (b)
Allele ChangesXba 1 Trivial nameEffectEnzyme activity
haplo-type(kb) In_vivo In_vitro
11.5 or 13 CYP2D6D CYP2D6
None (d, s)
CYP2D6*6A1707T>del29 CYP2D6T Frameshift None (d, dx)
None (s, d)
CYP2D6*7 2935A>C 29 CYP2D6E H324P None (s)
CYP2D6G Stop codon
Allele ChangesXba 1Trivial nameEffectEnzyme activity
BENNY K. ABRAHAM AND C. ADITHAN
29CYP2D6C K281delDecrease (b,s,d)Decrease
44, 29CYP2D6J P34S;
44,29 CYP2D6Ch 1P34S;
Decrease (d)Decrease (b)
29 CYP2D6F Splicing
Exon 1 CYP2D7,
29Frameshift None (dx)
CYP2D6*15 138insT29FrameshiftNone (d, dx)
11CYP2D6D2 FrameshiftNone (d)
29 CYP2D6Z T1071;
Decrease (d) Decrease (b)
CYP2D6*18 9 bp insertion
29 CYP2D6(J9)Decrease (s)Decrease (b)
Allele ChangesXba 1 Trivial nameEffect Enzyme activity
CYP2D6*2282C>T M2 R28C
CYP2D6*23 957C>TM3 A85V
CYP2D6*25 3198C>GM7 R343G
CYP2D6*27 3853G>AM9 E410K
CYP2D6*33 2483G>TCYP2D6*1C A237S Normal (s)
CYP2D6*34 2850C>T CYP2D6*1D R296C
Allele ChangesXba 1Trivial name Effect Enzyme activity
BENNY K. ABRAHAM AND C. ADITHAN
in exon 9
Decrease (d)Decrease (b)
b, bufuralol; d, debrisoquine; dx, dextromethorphan; s, sparteine
§ = Source: Homepage of the human cytochrome P450 (CYP) allele nomenclature committee.
Editors: Ingelman-Sundberg M, Daly AK and Nebert DW. (URL:http://www.imm.ki.se/cypalleles)
AlleleChanges Xba 1Trivial name EffectEnzyme activity
In allele specific PCR amplification, oligonucleotides
specific for hybridizing with the common or variant
alleles are used for parallel amplification reactions.
Analysis for the presence or absence of the appro-
priate amplified product is accomplished by agarose
gel electrophoresis49, 50.
These genotyping methods require small amount of
blood or tissue, are not affected by underlying dis-
eases or drugs taken by the patient and provide re-
sults within 48-72 hours, allowing for rapid interven-
tion3. The number of known defective alleles is
growing and a total of more than 30 different defec-
tive CYP2D6 and 55 CYP2D6 variations have been
identified18 (a current list of CYP2D6 alleles are given
in Table-2). However, it appears that depending on
the ethnic group, genotyping for only 5-6 most com-
mon defective alleles will predict the CYP2D6 phe-
notype with about 95-99% certainty18, 51. For exam-
ple, the most common CYP2D6 variant alleles in the,
Caucasian52, Chinese/Japanese53 and Black African/
Afro-American18 population are CYP2D6*4, *10 and
Racial and ethnic studies of drug metabolism have
shown substantial inter-population differences in the
polymorphic distribution of CYP2D6 activity and cor-
responding genetic materials. The prevalence of PM
and UEM in different ethnic groups is shown in Table
3 and 4. This polymorphism has been extensively
studied in Caucasians and Orientals with results con-
sistently showing a prevalence of PMs of 5-10% in
Table 3. Prevalence of CYP2D6 poor metabolisers in different ethnic groups (phenotyping).
Ethnic groupprobeTotal subjects PM (%)Reference
(Lapps)db 70 5.6131
BENNY K. ABRAHAM AND C. ADITHAN
Sri Lanka (Sinhalese)
Andhra Pradesh (Kakinada)
db=debrisoquine, sp= sparteine, dx= dextromethorphan, mp= metoprolol, cd= codeine.
Ethnic group probe Total subjectsPM (%) Reference
Caucasians (Europeans and white North Americans)
and 1% in Orientals (Chinese, Japanese and
Koreans). In these populations, there is a high corre-
lation of metabolic ratios with different probe drugs for
CYP2D6. The studies, which compared Oriental popu-
lation with Caucasians, showed an interethnic differ-
ence in the metabolism of CYP2D6 substrates54-56.
However, studies in African populations have yielded
inconsistent results with prevalence of PMs ranging
from 0-19%57. There seems to be a regional varia-
tion among African population. The wide variation in
the CYP2D6 phenotype in black Africans suggest that
the black population is not genetically homogeneous
as is often assumed57. Moreover, in some African
populations, there is a lack of metabolic co-segrega-
tion of different CYP2D6 probe drugs57, 59.
The ultra extensive metabolisers (UEM) are reported
with a prevalence of 1.5-29% in different ethnic
groups. The frequency of the CYP2D6 gene duplica-
tion was found to be 2-3% among most European
populations and a proportion of 12% in Turkish sub-
jects. The carriers of gene duplication in Saudi Ara-
bia60 and Ethiopia61 are 21% and 29% respectively.
The mechanism behind this high proportion of UEM
awaits further elucidation.
In India, an earlier study using debrisoquine, among
subjects resident in Bombay, reported 2% PM with
Table 4. Frequencies of poor metabolisers and the CYP2D6 gene duplication in genotyped population.
Ethnic groupTotal subjects PM (%)MxN (%) Reference
White North Americans
Black North Americans
PM = Poor metabolisers; MxN = Ultra extensive metabolisers (Gene duplication)
respect to CYP2D6 62. A much more recent study
with dextromethorphan showed a frequency of 3%
PM in a North Indian population63. In South India,
subjects from Kerala64, Karnataka65, Andhra
Pradesh65 and Tamil Nadu156 have been phenotyped
in our laboratory using dextromethorphan as probe
drug. In Kerala the PM frequency is 4.8%, Karnataka
4%, Andhra Pradesh 1.8% and in Tamil Nadu it is
3.6%. The average prevalence of PM in South India
is 3.52% (with 95% confidence interval of 2.03-
5.66%) which is higher than that reported with the
Chinese (0-1%) population and lower than Cauca-
sians (5-10%)65. A similar study also has been re-
ported with Hyderabad City population and the PM
frequency observed was 3.2% 66.
DNA marker studies reported that Indian and Euro-
pean populations have a common Caucasoid ances-
tor and are genetically distinct from those of Oriental
population67. However, the studies of CYP2D6 activ-
ity in India show that the Indian population is a sepa-
rate group with the enzyme activity in between the
Caucasian and Oriental subjects. The study of
CYP2C19 polymorphism in North Indian subjects
(11%) also indicated that cytochrome P-450 activity
in Indian population is different from other ethnic
groups68. However very less information is available
about the genetic analysis of CYP2D6 gene in In-
dian population. Since UEM cannot be determined
by only phenotyping, the prevalence of UEM in In-
dian population is not available.
Polymorphic drug oxidation
If sparteine and debrisoquine were the only drugs
affected by CYP2D6, the discovery of this poly-
morphism in drug oxidation would have been of theo-
retical interest because both these drugs cannot be
regarded as essential drugs. However, further stud-
ies identified a variety of structurally different com-
pounds, which are metabolized by the CYP-2D6 en-
zyme. A current list is provided in Table 5.
Although CYP2D6 is only a relatively minor form in
human liver (1.5% of total cytochrome-P450 iso-
forms), it metabolizes upto one quarter of all pre-
scribed drugs. This may be because many of the
drugs metabolized by CYP2D6 are targeted to the
central nervous system69.
BENNY K. ABRAHAM AND C. ADITHAN
Table 5. Substrates of CYP2D6.
Azelastine Cinnarizine LoratadinePromethazine
Brosen and Grams suggest70 that clinical significance
of polymorphism can be evaluated by asking the fol-
lowing questions: Does the kinetics of an active prin-
ciple of a drug depend significantly on a specific en-
zyme? Dose the resulting pharmacokinetic variabil-
ity have any clinical importance? Can the variation in
response be assessed by direct clinical or paraclinical
measurement? On the basis of these criteria, signifi-
cance exists for those drugs for which plasma con-
centration measurement are considered useful and
for which the elimination of the drug and/or its active
metabolite is mainly determined by CYP2D6 en-
The PM trait is characterized clinically by an impres-
sive deficiency in forming the relevant metabolite(s)
of affected substrate, which can result in either drug
toxicity or inefficacy. The reverse in case of UEM3.
The polymorphism of CYP2D6 is clinically more sig-
nificant for tricyclic antidepressants, certain
neuroleptics, antiarrhythmics, antihypertensives,
β-blockers and morphine derivatives25. For tricyclic
antidepressants, both the PM and UEM phenotypes
of CYP2D6 are at risk of adverse reactions47. PM
individuals given standard doses of these drugs will
develop toxic plasma concentrations, potentially lead-
ing to unpleasant side effects including dry mouth,
hypotension, sedation and tremor or in some cases
life threatening cardiotoxicity3.
For example, it has been reported that identical dos-
ing regimen of imipramine in EM and PM patients
showed the absolute concentrations of both the par-
ent drug (imipramine) as well as its desmethyl
metabolite (desipramine) are greater in PM individu-
als, resulting in reduced ratio of parent drug to
metabolite in them71-73. Here the N-methylation of
imipramine to its pharmacologically active desmethyl
metabolite desipramine is catalyzed primarily by
CYPC19, and CYP1A2, where as the 2-hydroxylation
of desipramine to its pharmacologically inactive
metabolites is catalyzed by CYP2D6 3, 71.
Administration of CYP2D6 substrates to UEM indi-
vidual may result in therapeutic failure because
plasma concentrations of active drug at standard
doses will be far too low74. The clinical presentation
of UEM and PM patients are at times similar, lead-
ing to confusion in understanding the basis of ad-
verse drug reaction. Because of lack of dose indi-
vidualization, patients may be subjected to recur-
rent depressive episodes and may not respond to
treatment. Patients requiring treatment with antide-
pressant or antipsychotic substrates of CYP2D6
may begin the normal treatment regimen. Because
of the long half-life of these drugs, toxic drug con-
centrations may take 5-7 weeks to develop. There-
fore, it is suggested that the patients should be
phenotyped before starting the treatment with drugs
which are metabolized mainly by CYP2D6 enzyme3.
A recent US study showed that, in patients pre-
scribed with psychiatric drugs that are CYP2D6
substrates, adverse drug reactions were observed
in every patient with inherited mutations inactivat-
ing the CYP2D6 gene75.
A lack of CYP2D6 enzyme would be expected to re-
sult in reduced drug therapy effectiveness in in-
stances where prodrugs requiring activation by
CYP2D6 are used. For example, the analgesic ef-
fect of tramadol is severely reduced in PMs76. Simi-
larly, following administration of the prodrug codeine,
morphine could not be detected in the plasma of
CYP2D6 PMs 77-79. On the contrary, severe abdomi-
nal pain, a typical adverse effect of morphine, was
observed in all UEM treated with codeine18. Moreo-
ver, codeine produced prolongation of the orocae-
cal transit time only in EM subjects80.
Due to the high polymorphic character of CYP2D6,
this enzyme is also the site of a number of drug in-
teractions in vivo, which are of clinical significance.
Substrates with a high affinity for the enzyme bind
strongly to it and inhibit the metabolism of other com-
pounds which have lower affinity. Consequently drug
interaction occur in extensive as well as poor
metabolisers47. By using this knowledge, pharma-
cokinetic interactions can be anticipated as follows:
If drug A affects P450 enzyme X and if P450
enzyme X metabolises drugs B, C and D, then
drug A should affect the metabolism of drug B,
C and D.
This type of knowledge is also being used to decide
which drugs to develop, because the inhibition of
P450 enzyme is generally not the goal of treatment81.
The interaction of two substrates for CYP2D6 can
result in a number of clinical responses. The first pass
metabolism of the substrate may be inhibited or the
rate of elimination may be prolonged such that higher
plasma concentration and associated pharma-
codynamic responses may occur5, 47, 82-86.
Inhibition of metabolism by CYP2D6 can also lead
to a lack of therapeutic response when the pharma-
cological action is dependent on the active
metabolite3, 87. Since CYP2D6 is not inducible by en-
zyme inducing drugs, drug interactions due to en-
zyme induction are very unlikely to occur47.
PATHOPHYSIOLOGICAL ASPECTS OF CYP2D6
Involvement of CYP2D6 and its variant alleles in the
pathogenesis of certain diseases (either by activat-
ing xenobiotics or by involvement in neurotransmit-
ter metabolism) is an interesting and yet unsettled
area of research.
BENNY K. ABRAHAM AND C. ADITHAN
CYP2D6 polymorphism has been linked to suscepti-
bility to various diseases including certain cancers,
early onset of Parkinson’s disease, systemic lupus
erythematosus, pituitary adenomas, Balkon
nephropathy and ankylosing spondylitis1, 19, 88-90. Meta-
bolic activation of a procarcinogen may proceed via
CYP2D6 which implies that a patient of extensive
metaboliser phenotype forms higher amounts of the
active compounds and therefore at a higher risk to
develop cancer11. The CYP2D6 gene is responsible
for the metabolism of known human carcinogens,
including nitrosamines and, possibly, nicotine. In ad-
dition it is suggested that there may be endogenous
substrates for CYP2D6, including tryptamine, a well-
known neuroactive amine90. However, the influence
of CYP2D6 allelic variance in different types of can-
cer is a controversy. When some studies suggested
a role for CYP2D6 in the development of cancer,
several studies could not support this91, 92.
A variety of studies investigated a possible link of Par-
kinsonism to CYP2D6 expression93-96. Other studies
however, failed to show any relation of CYP2D6 activity
and Parkinsonism97, 98. These trials have been performed
in different ethnic groups and as P450 gene structures
show interethnic group differences, comparison of these
experiments and extrapolation for one ethnic group to
another appears to be rather questionable11.
Thus determination of these genetic polymorphism
may be of clinical value in predicting adverse or
inadequate response to certain therapeutic agents
and in predicting increased risk of environmental or
occupational exposure-linked disease. The
genotyping/phenotyping will lead to increased thera-
peutic efficacy, improved patient outcome and thus
more cost-effective medication3, 99, 100.
MOLECULAR GENETICS IN CLINICAL
In place of simple descriptive information provided
by therapeutic drug monitoring, molecular genetics
could produce information about why a patient may
require a different dose, drug or treatment regimen
before a therapy is instituted100, 101. It might also sub-
stantially reduce the need for hospitalization because
of adverse drug reactions and its associated costs3.
Pharmacogenetic testing is currently used in only a
limited number of teaching hospitals and specialist
academic centers. It is well established in
Scandinavian countries. The most widely accepted
application of pharmacogenetic testing is the use of
CYP2D6 genotyping to aid individual dose selection
for drugs used to treat psychiatric illness. Several
independent testing laboratories provide DNA based
testing service for a range of pharmacogenetic
polymorphisms to pharmaceutical industry and medi-
cal practice75. However, in India, this system has not
The advantage of combining genotyping/phenotyp-
ing with therapeutic drug monitoring is that
genotyping can predict the PM or UEM drug metabo-
lism phenotypes, and this information can be used
for dosage adjustment or selection of an alternative
drug, which is not a substrate of CYP2D6. The cost/
healthcare effectiveness of these paradigms has not
been extensively studied. Although there would be
considerable cost associated with screening all indi-
viduals before dosing with CYP2D6 substrates of
narrow therapeutic index, this cost may be offset by
a reduction in costs associated with toxic episodes
or therapeutic failure and subsequent intervention3.
Polypharmacy and over the counter drug purchase
is very common in developing countries like India and
Sri Lanka. Since CYP2D6 is responsible for the me-
tabolism of most of the commonly used drugs, this
may result in severe drug interactions especially in
the poor metabolisers. Routine phenotyping or
genotyping may not be economical in developing
countries. However, monitoring of CYP2D6 enzyme
activity is important for the patients who report ad-
verse reactions with normal dose of the drugs. This
may help the physicians in individualization of the
therapy especially for long term drugs like anti-de-
pressants and anti-hypertensive70.
Since genotyping is more costly procedure than
phenotyping and not commonly available in most of
the hospitals, the latter is more preferred for routine
analysis in developing countries. However, for pa-
tients undergoing concomitant therapy with the drugs,
which can affect on CYP2D6 activity, genotyping may
IMPLICATION FOR DRUG DEVELOPMENT
The knowledge gained about these polymorphism
studies should be incorporated into drug develop-
ment at an early stage to determine whether or not
the drug is metabolized by CYP2D6 and hence
subject to genetic polymorphism. Since phase-1 clini-
cal trials are carried out at a rather later time during
drug development, usually five to seven years after
the initial discovery, a strategy, which allows for an
earlier recognition of this phenomenon would be de-
sirable47. Dosing regimens are normally established
during the phase-1 evaluation of drugs and are based
on studies of relatively small number of subjects.
However, with respect to oxidation phenotype, this
subjects may not be representative of the general
If it were possible to predict that the metabolism of a
drug cosegregates with a known polymorphism at
the preclinical stage, the decision on whether or not
to pursue development of the drug would be facili-
tated47. Several in vitro approaches have been de-
veloped which allow a prediction to be made during
preclinical testing if the metabolism of a new drug is
subject to genetic polymorphism102, 103. Inhibitory
monoclonal antibodies are available which determine
cytochrome P450 substrate and product specificity104,
105. It is obviously also prudent to exclude potentially
susceptible individuals from phase-1 dose escala-
tion trials. This can prevent PM healthy subjects or
patients being exposed to additional risk of toxicity
during phase-1 and 2 development1.
There is currently great interest in the pharmaceuti-
cal industries in pharmacogenetics and an increas-
ing number of companies are genotyping their
clinical trial populations. Moreover, the knowledge of
genetic variability in drug response is becoming an
increasingly important component of the drug regis-
Although the potential importance of genetic variabil-
ity in drug response is generally acknowledged in
academic circles, the pharmaceutical industry and
the drug regulatory authorities, this is not yet the case
in general practice and, indeed, in many clinical phar-
macology departments. A greater awareness of this
urgently needed. Since many of the drug metabo-
lized by CYP2D6 are CNS active agents with narrow
therapeutic indices, drug over treatment and accu-
mulation can give rise to symptoms similar to those
of the disease itself. Doctors need to be aware of
whether a drug they are prescribing is subject to
pharmacogenetic variability and its importance and
potential drug interactions. Prescribing advice should
highlight the possibility of drug interactions when
multiple drugs are prescribed concomitantly.
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PROBIOTIC MILK MAY HELP PREVENT COMMON CHILDHOOD INFECTIONS
Probiotic milk (milk containing bacteria that colonise the intestine and stimulate antibody production) may slightly reduce
respiratory infections among children attending day care centres, finds a study in BMJ. These findings suggest that these
bacteria may help prevent common infections, particularly in high risk children.
Over a seven month winter period, 571 children attending day care centres in Helsinki, Finland received milk with or without
the probiotic bacteria strain Lactobacillus GG. During the study, parents recorded any respiratory symptoms (fever, runny
nose, sore throat, cough, chest wheezes, earache) gastrointestinal symptoms (diarrhoea, vomiting, stomach ache) and
absences from the day care centre.
Although there were no significant differences between the groups in the number of days with respiratory or gastrointestinal
symptoms, the actual number of days with symptoms was lower in the Lactobacillus group. Children in the Lactobacillus
group also had fewer days of absence because of illness and required less antibiotic treatment.
Although encouraging, we do not yet have a final answer on whether probiotics are sufficiently effective in preventing
common childhood diseases that they can be routinely recommended, writes Professor Christine Wanke of Tufts University
School of Medicine in Boston, USA. However, she concludes: “the accumulating data suggest that these organisms may
help prevent both respiratory and diarrhoeal diseases in children at increased risk of such infections, such as those in day
care facilities or living in developing countries.”
(Effect of long term consumption of probiotic milk on infections in children attending day care centres: double blind,
randomised trial. http://bmj.com/cgi/content/full/322/7298/1327)