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Pharmacogenetics of Neonatal Opioid Toxicity
Following Maternal Use of Codeine During
Breastfeeding: A Case–Control Study
P Madadi1,2, CJD Ross3, MR Hayden3, BC Carleton4, A Gaedigk5, JS Leeder5 and G Koren1,2,6
A large number of women receive codeine for obstetric pain while breastfeeding. Following a case of fatal opioid
poisoning in a breastfed neonate whose codeine prescribed mother was a CYP2D6 ultrarapid metabolizer (UM), we
examined characteristics of mothers and infants with or without signs of central nervous system (CNS) depression
following codeine exposure while breastfeeding in a case–control study. Mothers of symptomatic infants (n = 17)
consumed a mean 59% higher codeine dose than mothers of asymptomatic infants (n = 55) (1.62 (0.79) mg/kg/day vs.
1.02 (0.54) mg/kg/day; P = 0.004). There was 71% concordance between maternal and neonatal CNS depression. Two
mothers whose infants exhibited severe neonatal toxicity were CYP2D6 UMs and of the UGT2B7*2/*2 genotype. There
may be a dose–response relationship between maternal codeine use and neonatal toxicity, and strong concordance
between maternal-infant CNS depressive symptoms. Breastfed infants of mothers who are CYP2D6 UMs combined with
the UGT2B7*2/*2 are at increased risk of potentially life-threatening CNS depression.
INTRODUCTION
Nearly half of all infants born in North America are delivered by
caesarean section or after episiotomy. Codeine-containing medications are commonly used for pain associated with these procedures.1 An estimated 80% of mothers initiate breastfeeding. On
the basis of these statistics, up to 40% of breastfeeding mothers
in North America may be prescribed codeine for pain associated
with childbirth.2,3 The American Academy of Pediatrics recommends codeine as being compatible with breastfeeding.4 This
recommendation is based on several studies in which levels of
codeine in breast milk were measured and found to be low.5–7
Codeine is a prodrug, and its analgesic properties are primarily dependent on its biotransformation into morphine by the
cytochrome enzyme P450 2D6 (CYP2D6). The production of
morphine normally accounts for 10% of total codeine metabolism.8 Morphine is mainly glucuronidated into the inactive
morphine-3-glucuronide, while a small fraction is conjugated
into the active morphine-6-glucuronide (M6G). The production of M6G is almost exclusively catalyzed by the enzyme
uridyl glucuronosyltransferase 2B7 (UGT2B7),9 while several
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isoforms of the uridyl glucuronosyltransferase 1A subfamily, as
well as UGT2B7, are involved in the formation of morphine-3glucuronide.10 Hence, genetic variability in CYP2D6, and possibly in UGT2B7, may affect the efficacy and toxicity of codeine.
Polymorphisms in CYP2D6, and to a lesser extent in UGT2B7,
have been the subject of much recent investigation. Of particular
interest is CYP2D6 gene duplication, leading to the ultrarapid
metabolizer (UM) phenotype if the duplicated genes are fully
active and if the duplication is combined with another active
CYP2D6 allele.11 Case reports of adults with the UM phenotype have described opioid toxicity even with small doses of
codeine.12,13 In full-term neonates, CYP2D6 activity appears to
be concordant with genotype at 2 weeks of age.14
The UGT2B7*2 variant arises from a single-nucleotide polymorphism in the coding region of the gene (802 C→T exon 2).15
One study reported that adults who were homozygous for the
UGT2B7*2 allele had higher M6G: morphine ratios than those
who are homozygous for the wild-type allele (*2/*2 > *1/*2 >
*1/*1).16 In neonates, UGT2B7 activity is initially low at birth
and reaches adult levels by 2–6 months of age,17 so the effects of
1Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario, Canada; 2The Ivey Chair in Molecular Toxicology, University of Western
Ontario, London, Ontario, Canada; 3Centre for Molecular Medicine and Therapeutics, Vancouver, British Columbia, Canada; 4Pharmaceutical Outcomes and Policy
Innovations Program, University of British Columbia, Vancouver, British Columbia, Canada; 5Section of Developmental Pharmacology and Therapeutics, Children’s
Mercy Hospital, Kansas City, Missouri, USA; 6Motherisk Program, Hospital for Sick Children, Toronto, Ontario, Canada. Correspondence: G Koren ([email protected])
or ([email protected])
Received 28 May 2008; accepted 26 June 2008; advance online publication 00 Month 2008. doi: 10.1038/clpt.2008.157
CLINICAL PHARMACOLOGY & THERAPEUTICS
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these polymorphisms is less pronounced. Since M6G is at least
equipotent to morphine, the UGT2B7*2/*2 variant, in combination with the CYP2D6 UM phenotype, may contribute to
higher production of pharmacologically active opioids following codeine exposure.
The overall percentage of Western Europeans with the
CYP2D6 UM phenotype is 5.45% (range 1–10% depending on
country of origin),18 while higher frequencies have been reported
among those with northeast African and Middle Eastern ancestry (e.g., 16% in Ethiopians and 10% in Saudi Arabians).19,20
Homozygosity for UGT2B7*1 and UGT2B7*2 is approximately
equal in Caucasian populations at a frequency of 27.5 and 25.3%,
respectively.21 In contrast, homozygosity for UGT2B7*1 is over
10 times more prevalent than UGT2B7*2 in the Japanese.21
On the basis of the available frequencies, one can estimate that
the combination of CYP2D6 UM and UGT2B7*2/*2 genotype
would be found, on average, in 1.4% (range 0.25–2.5%) of individuals with Western European ancestry.
Following a case of fatal neonatal opioid toxicity in an infant
breastfed by a CYP2D6 UM mother,22,23 we sought to investigate
the prevalence of opioid toxicity in breastfed infants and the
mechanisms underlying such toxicity. Our objectives were to
compare genetic and nongenetic characteristics of mothers and
babies with or without signs of central nervous system (CNS)
depression following exposure to codeine while breastfeeding.
Table 1 Maternal codeine indication and infant age when first
exposed to codeine in symptomatic and asymptomatic infants
Symptomatic Asymptomatic
infants (n = 17) infants (n = 55)
P value
Maternal codeine indication, no. (%)
Caesarean section
7 (41%)
18 (33%)
0.42
Vaginal/episiotomy
5 (29%)
10 (18%)
0.31
Headache/migraine
1 (6%)
8 (15%)
0.36
Colorectal/dental surgery
2 (12%)
8 (15%)
0.73
Chronic disease
1 (6%)
3 (5%)
0.67
Other
1 (6%)
8 (15%)
0.36
14 (82%)
31 (56%)
0.25
2 weeks to 2 months
1 (6%)
11 (20%)
0.21
2–9 months
2 (12%)
13 (24%)
0.31
Infant age at codeine exposure
<2 weeks
Table 2 Demographics of mothers and their symptomatic or
asymptomatic infants
Symptomatic Asymptomatic
infants (n = 17) infants (n = 55) P value
Demographic characteristics, mean (SD)
Infant birth weight (kg)
3.55 (0.60)
3.48 (0.60)
0.32
Gestational age (weeks)
39.4 (1.6)
39.2 (1.7)
0.38
RESULTS
Maternal age (years)
31.7 (3.6)
34.9 (4.5)
0.99
All callers who were counseled about codeine use during breastfeeding by the Motherisk Program between January 2004 and
January 2007 were identified (n = 394), and consenting mothers
who were accessible by telephone were contacted (n = 171). Of
those, 99 women were excluded from the study because they
either did not take codeine (n = 60), used codeine in a cough
syrup formulation (n = 13), or took other CNS-acting medications in addition to codeine (n = 26). Seventy-two mothers
consented to participate in the telephone interview and genetic
analysis, and they constituted this study cohort.
Out of the cohort of 72 mother–child pairs, 17 (24%) breastfed infants were reported to exhibit CNS depression while their
mothers used codeine. In all 17 cases of neonatal CNS depression, the parents reported an observable decrease in the infant’s
alertness while breastfed with codeine, and a notable improvement after codeine (or breastfeeding) was discontinued.
More than half of the women enrolled in the study consumed codeine following caesarian section or vaginal delivery (with episiotomy). The rest of the women took codeine for
nonobstetric indications such as headache or dental surgery.
Symptomatic infants tended to be younger than 2 weeks of age
at the time of codeine exposure, which was not statistically
significant (Table 1).
The distribution of cases with neonatal CNS depression was
similar to that of asymptomatic cases on parity, infant birth
weight, maternal and gestational age, breastfeeding frequency
and duration, infant’s age when breastfed on codeine, formula
supplementation, and ethnic distribution. Infants with CNS
depression were significantly more likely to visit the emergency
Parity (offspring)
2.06 (0.9)
1.65 (0.94)
0.94
Maternal codeine dose
(mg/kg/day)
1.62 (0.79)
1.02 (0.54)
0.004*
5 (29%)
6 (11%)
2
Non-Caucasian ethnicity, no. (%)
0.12
bInfant ER visits, no. (%)
4 (24%)
0 (0%)
Formula supplementation, no.
(%)
7 (41%)
18 (33%)
Breastfeeding duration, median
(min − max), day
7 (2–180)
4 (1–180)
0.24
Breastfeeding frequency,
median (min − max), times/day
8 (3–12)
8 (1–12)
0.22
0.002*
0.42
ER, emergency room.
*P < 0.05; statistically significant.
room for an adverse event (lethargy, breathing difficulties, and/
or poor feeding) during the period of codeine exposure as compared to asymptomatic infants (Table 2).
Mothers whose infants exhibited CNS depression received, on
average, 59% higher daily doses of codeine per kg body weight
as compared to mothers whose babies did not exhibit adverse
CNS effects (1.62 ± 0.79 mg/kg/day vs. 1.02 ± 0.54 mg/kg/day
(P = 0.004)).
There was good concordance between maternal and infant
CNS depression: when the baby exhibited CNS depression, there
was a 71% probability (12/17) that the mother also exhibited
such signs. When the baby did not exhibit CNS depression, only
5/55 mothers exhibited CNS depression (9%).
Mothers who exhibited CNS depression consumed 1.29 ±
0.72 mg/kg/day codeine, which was not statistically different
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Table 3 CYP2D6 and UGT2B7 genotypes of mothers with
proposed CYP2D6 ultrarapid metabolizer phenotype
Mothers of symptomatic infants
(n = 2)
Mother of asymptomatic infants
(n = 1)
1. CYP2D6*2A/*2A(Dup), UGT2B7*2/*2 1. CYP2D6*1/*1XN, UGT2B7*2/*1
2. CYP2D6*2/*2A(Dup), UGT2B7*2/*2
Dup, duplication.
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from those not exhibiting CNS depression (1.05 ± 0.53 mg/kg/
day (P = 0.89)).
Two (11.8%) mothers of symptomatic infants were CYP2D6
UMs in combination with UGT2B7*2/*2 genotype, as compared
to 0% of mothers among nonsymptomatic infants (Table 3).
Mothers of symptomatic cases were more than eight times more
likely to have the combined genotype than the average expected
Western European population frequency of 1.4% (odds ratio 8.4;
95% confidence interval 4.7–47; P ≤ 0.001).
In the first case, described by us separately,22 a new mother
was prescribed Tylenol #3 (500 mg acetaminophen and 30 mg
codeine) for pain associated with an episiotomy. She began taking 120 mg/day codeine but halved the dose to 60 mg/day on
day 2 due to maternal somnolence and constipation. Her infant
developed difficulty in breastfeeding and showed increasing
lethargy on day 7. At 11 days of age, he was taken to a pediatrician owing to concerns about his gray skin color and decreased
milk intake. The doctor noted that the infant had regained his
birth weight. Subsequently, on day 13, an ambulance team found
the baby cyanotic and without vital signs. Postmortem analysis
revealed a toxic blood morphine concentration of 70 ng/ml in
the infant. Maternal breast milk obtained on day 10 of the baby’s
life contained 87 ng/ml of morphine.
In the second case, the breastfeeding mother took 120 mg/
day codeine (Tylenol #3) for severe muscle pain after childbirth.
She reported feeling sedated, nauseous, dizzy, and weak during the period she was taking codeine. Her breastfed infant was
described as extremely drowsy and feeding poorly. She began
supplementing breast milk with formula after delivery because
of personal exhaustion and due to her infant’s feeding difficulties.
The family doctor was contacted with concerns about the infant’s
condition. By 7 days after delivery, the mother had switched
completely to formula feeding, and she noted complete reversal
of the infant’s symptoms in the following days. The mother continued taking codeine-containing medication for 3 weeks after
switching to formula feeding.
One asymptomatic case was a CYP2D6 UM in combination
with UGT2B7*2/*1 genotype (Table 3). The mother had taken
60 mg/day codeine (Tylenol #2) for 1 week following removal of
her appendix when her breastfed baby was 6 months old. At that
stage the baby was also receiving formula and solid foods.
DISCUSSION
Although codeine has been recommended by the American
Academy of Pediatrics as being compatible with breastfeeding,4
there have been previous reports suggesting that this may not be
the case. A prospective follow-up of adverse reactions in breastfed infants exposed to maternal medication found that 5 of 26
CLINICAL PHARMACOLOGY & THERAPEUTICS
mothers (19.2%) who were taking codeine with acetaminophen
reported drowsiness in their infants.24
A 1984 abstract cited four near-term breastfed infants who
exhibited neonatal apnea attacks which started 4–6 days following administration of 60 mg codeine (q 4–6 h) to breastfeeding
mothers. When breastfeeding was halted for 24 h and codeine
use was discontinued, apnea resolved within 24–48 h and the
infants were discharged.25 Another abstract reported that 10 of
12 full-term infants who had unexplained episodes of apnea,
bradycardia, and/or cyanosis occurring in the hospital between
0.5 and 7 days of age were exposed to opioids through breast
milk, and that 6 of the 12 infants were specifically exposed to
codeine in breast milk.26 Neither of these abstracts, written over
20 years ago, was subsequently fully published.
Maternal genotype was a significant factor associated with
neonatal CNS depression, but it was not the sole predictor in all
breastfed infants. Mothers of infants who were CNS depressed
took significantly higher doses of codeine than those of nonCNS-depressed infants. The lowest maternal dose of codeine
associated with symptoms in the infant was 0.63 mg/kg/day,
which translates to 44 mg codeine (i.e., three tablets of Tylenol
#2 or 1.5 tablets of Tylenol #3) for a 70 kg woman.
The mothers in the two cases described had combined genotype alterations of both CYP2D6 UM and UGT2B7*2/*2 and
had consumed high doses of codeine (2.13 and 2.18 mg/kg/day).
These doses, when combined with their genetic predisposition
to excessive production of morphine and its active metabolite
M6G, may explain the severe neonatal toxicity including infant
fatality in one case. The other mother supplemented with formula starting postnatal day 1, and had discontinued breastfeeding completely by day 7, thereby probably preventing severe
consequences of neonatal toxicity.
The postmortem morphine concentration in the baby who died
is consistent with concentrations reported in postmortem cases in
which the deceased had received high opioid doses.27 Concurrent
with a morphine milk concentration seven times higher than ever
described from maternal codeine use, this suggests excessive
morphine consumption through breast milk. It is not possible
to estimate the accurate morphine dose offered to the infant in
this case, as only one milk concentration was available, and this
sample was obtained only after the mother had halved her dose.
Moreover, there may be postmortem fluctuations in morphine
concentrations, although the measured level was fourfold higher
than concentrations that cause respiratory depression in babies.
Mothers of symptomatic infants were six times more likely
than those of asymptomatic infants to be CYP2D6 UMs. The
true odds ratio is probably higher, because the only CYP2D6
UM mother in the asymptomatic group was breastfeeding
a 6-month-old infant who received formula and solid foods
during the period of maternal codeine use. Hence, this infant
likely avoided the risks associated with his mother’s genotype.
Furthermore, this infant was better able to metabolize morphine
than infants exposed to codeine during the first week of life.17
In both symptomatic cases exhibiting a combination of CYP2D6
UM and UGT2B7*2/*2 genotype, it was after 7 days of breastfeeding that the infant’s adverse effects became apparent. This agrees
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with previous reports25,26 and is well explained by the slow accumulation of steady-state levels of morphine, given its long elimination half-life in neonates.28 Hepatic and renal physiology change
markedly during the first week after birth, with neonates aged 7
days and younger requiring significantly less morphine postoperatively than older neonates.29 This finding supports a clinical
strategy of limiting codeine use to a few days in order to avoid
morphine accumulation and the onset of CNS depression.
The relationship between interindividual differences in morphine glucuronidation and UGT2B7 genetic variation is not yet
clear. Individuals receiving intravenous morphine who were
homozygous for the UGT2B7*2 allele have been reported to
have higher M6G levels than those who are homozygous for the
wild-type allele.16 In contrast, in a study of 175 cancer patients
receiving oral morphine therapy, no correlation between
UGT2B7 genotype and morphine glucuronide-to-morphine
serum ratios was detected.30
While maternal polymorphism in CYP2D6 and UGT2B7 are
important in considering the pharmacokinetics of codeine and
its subsequent excretion into breast milk, genetic differences
in pharmacodynamic parameters, such as transport across the
blood–brain barrier and polymorphism at the μ-opioid receptors,
can contribute to variability in morphine analgesia. However, the
influence of these polymorphisms in neonates is not yet clear.
Following the publication of the first symptomatic case from
this study,22 the Food and Drug Administration issued a public health advisory warning that the use of codeine by nursing
mothers who are CYP2D6 UMs may increase the risk of serious
adverse effects in some breastfed infants.31 This study further
corroborates that codeine cannot be considered a safe drug during breastfeeding for all infants.
The Motherisk Program is uniquely situated to investigate the
risks associated with drugs in breast milk. This is one of very few
programs worldwide that prospectively collect data from breastfeeding mothers and follow-up infants longitudinally. However,
this study has several potential limitations that need to be
addressed. Being a retrospective study, recall by parents may not
be accurate. Moreover, detection of sedation and stupor in the
first weeks of life may be challenging, because these symptoms
are nonspecific. However, in all 17 cases of reported neonatal
CNS depression, the parents reported a distinct improvement in
infants’ alertness after exposure to codeine was discontinued.
Women who call the Motherisk Program are self-selected
and therefore the prevalence of CNS depression (17/72; 24%)
may not represent an accurate estimate of neonatal risk. For
this reason in this study we refrain from estimating the true risk
of neonatal CNS depression induced by maternal codeine use
during breastfeeding. To make such an estimate, a prospective
cohort study needs to be performed.
While our study clearly shows a dose-dependent effect on
neonatal opioid toxicity, the number of neonates with apparent toxicity (n = 17) was too small to establish a rigorous window of safety. Yet, the fact that apparent toxicity occurred with
a maternal dose as low as 0.63 mg/kg/day of codeine (corresponding to 1.5 tablets of Tylenol #3 for a 70 kg woman) should
serve as a reminder that the higher sensitivity of neonates to the
4
CNS-depressing effects of opioids may put some infants at risk
even with an apparently small maternal dose.32,33
In conclusion, our study suggests that there may be a dose—
response relationship between maternal codeine use and neonatal toxicity. Neonatal toxicity was reported with a daily maternal
dose of codeine as low as 0.63 mg/kg. Mothers with CYP2D6
UM genotype, when combined with UGT2B7*2/*2, may have a
high risk of neonatal opioid poisoning. Because of the gradual
accumulation of morphine in breastfed infants, it appears that
neonatal risk may increase with prolonged maternal codeine
use. If the mother needs codeine for long periods of time, it is
advisable that the baby be periodically monitored by an experienced pediatrician. Given the apparent concordance between
maternal and infant CNS symptoms, signs of maternal toxicity
may prompt examination for neonatal CNS depression. In any
suspected case of CNS depression in the infant, it is advisable
that the baby’s exposure to codeine be discontinued, followed
by physical and neurological examination.
METHODS
Patient recruitment. After approval by the Research Ethics Committee
at the Hospital for Sick Children (Toronto, Ontario, Canada), mothers from all parts of Canada who had been counseled between January
2004 and 2007 by the Motherisk Program (Toronto, Ontario, Canada)
about the use of codeine during breastfeeding were identified. The
Motherisk Program is an information and counseling service that
assesses maternal/fetal risks following exposure to medications, chemicals, and various environmental factors during pregnancy and lactation. In addition to reviewing the detailed intake forms documenting
each counseling session, all the women were followed up with a telephone interview within 1 year after the time of call. The interview consisted of a standardized questionnaire to assess a variety of maternal
and infant characteristics, including the signs of CNS depression in the
mother and infant during the period of codeine exposure as compared
to periods before and after codeine use.
Assessment of neonatal CNS depression. CNS depression in infants
was defined as parental reports of sedation or abnormal breathing in the
infant during the period of codeine exposure through breast milk. In all
cases we sought information comparing the behavior of the baby during
and after codeine exposure.
Inclusion and exclusion criteria. Women were included in the study
if they had taken codeine while breastfeeding, if they were ≥16 years of
age, and if they gave informed consent to participate in the telephone
interview and genotyping. Women were excluded from the study if they
had taken sedative medications concurrently with codeine while breastfeeding, if they had used drugs of abuse or alcohol while breastfeeding,
if their codeine use was limited to cough syrup formulations, if they had
used opioids in late pregnancy, or if the infants were diagnosed with
disorders of the CNS.
Genotyping. At the time of delivering the questionnaire, the women were
asked to provide DNA for genotype analysis of CYP2D6 and UGT2B7.
They were given written consent forms and Oragene saliva collection
cups labeled with barcode identification. Written consent letters were
returned to our office in self-addressed envelopes, while barcode-labeled
saliva collection cups were sent back in prepaid packages to our laboratory for DNA analysis.
CYP2D6 genotyping was conducted as previously described by
Sistonen et al. and Lovlie et al.34,35 Samples were followed up with
additional genotyping using the Tm Biosciences CYP2D6 Mutation
commercial kit to confirm gene duplication and to assess whether the
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duplicated gene was functional by testing for the presence of the 2D6*2,
2D6*2A, 2D6*3(A,B), 2D6*4(A-L), 2D6*5, 2D6*6(A-D), 2D6*7,
2D6*8, 2D6*9, 2D6*10(A,B), 2D6*11, 2D6*12, and 2D6*17 alleles.
Genotyping for the UGT2B7-161C>T (promoter) and 802C>T (exon
2) single-nucleotide polymorphisms associated with the UGT2B7*2 allele
were conducted using PCR-restriction fragment length polymorphism–
based assays:
Genomic DNA was amplified with the following primers: 5′-GTGA
ACAGATCATTTACCTTCATTTGgaTC (partial BamHI restriction site
in bold and mismatches in lower case) and 5′-CCTTTCCACAATTCC
CAGAG for –161C>T, and 5′-GTCCGTATGCTACTATTGAAGC
and 5′-TTGTGCTAATCCCTTTGTAAAT for 802C>T, respectively.
PCR fragments carrying –161C (reference sequence) were cut with
BamHI and yielded fragments of 26 and 241 bp, while the fragment carrying the variant 161T remained uncut. PCR products carrying 802C (reference sequence) were cut three times with BtsCI into 346-, 312-, 111-, and
38-bp fragments, and twice in the presence of 802T (457, 312, and 38 bp).
Restricted PCR products were separated on 1.5% agarose gels.
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11.
12.
13.
14.
15.
16.
17.
Statistical analysis. Infants exhibiting signs of CNS depression temporally related to codeine use during breastfeeding, and their mothers were
compared with those who did not exhibit CNS depression on maternal
and infant characteristics including daily maternal codeine dose per kilogram body weight, and CYP2D6 and UGT2B7 genotype. Unpaired t-test,
Mann–Whitney U-test, and Fisher exact tests were used as appropriate.
The data were analyzed using SAS Version 9.1. The data are expressed as
mean ± SD unless otherwise stated.
18.
ACKNOWLEDGMENTS
We thank Terry Pape for assistance with genotyping. This work was funded
by a grant from Genome British Columbia as part of the GenotypeApproaches to Therapies in Childhood (GATC) initiative. GK is holder of
the Research Leadership for Better Pharmacotherapy during Pregnancy
and Breastfeeding (Hospital for Sick Children, Toronto, Canada) and the
Ivey Chair in Molecular Toxicology (Department of Medicine, University
of Western Ontario). This work was presented at the 2008 meeting of the
American Society for Clinical Pharmacology and Therapeutics (ASCPT; April
2008, Orlando, FL). PM was awarded the ASCPT Presidential and Student
Awards for this work.
21.
CONFLICT OF INTEREST
The authors declared no conflict of interest.
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