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Journal of Analytical Toxicology 2014;38:404 –409
doi:10.1093/jat/bku051 Advance Access publication May 17, 2014
Article
Urinary Hydrocodone and Metabolite Distributions in Pain Patients
Neveen H. Barakat1, Rabia S. Atayee1,2, Brookie M. Best1,3 and Joseph D. Ma1,2*
1
University of California San Diego (UC San Diego), Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive,
MC 0714, La Jolla, CA 92093-0714, USA, 2Doris A. Howell Palliative Care Service, San Diego, CA, USA, and 3UC San Diego Department
of Pediatrics, Rady Children’s Hospital, San Diego, CA, USA
*Author to whom correspondence should be addressed. Email: [email protected]
Hydrocodone combined with acetaminophen is commonly used for
moderate pain. Hydrocodone is metabolized by cytochrome P450
(CYP) 2D6 into hydromorphone and by CYP3A4 into norhydrocodone.
This was a retrospective study evaluating hydrocodone, hydromorphone and norhydrocodone distributions in urine. Urine specimens
(n 5 76,924) were obtained from patients on chronic opioid therapy
during their first or single visit and were analyzed by liquid chromatography – tandem mass spectrometry (LC – MS-MS). The patients
were at least 16 years of age and had documented hydrocodone
use via a medication list. There were 48,710 specimens that were
positive for all three analytes. Mean hydrocodone, hydromorphone
and norhydrocodone mole fractions (95% confidence interval) were
0.39 (0.38–0.39), 0.12 (0.11–0.12) and 0.49 (0.48–0.49), respectively.
Hydromorphone fractions were lower in women compared with men
(0.11 versus 0.13; P < 0.0001). Hydrocodone mole fractions were
higher in the 65-year and older age group compared with the 16- to
39-year age group (0.4 versus 0.36; P 0.005). Concurrent use of a
CYP2D6 and/or CYP3A4 inhibitor altered hydromorphone and norhydrocodone mole fractions, compared with the control group. Patient
factors affect hydrocodone and metabolite mole fractions and suggest increased awareness of their contribution when attempting to
interpret urine drug testing results.
Introduction
Hydrocodone is a semisynthetic opioid that is structurally related
to codeine. Hydrocodone stimulates the mu-opioid receptor, inhibits the release of transmitters from sensory neurons and alters
pain transmission. In 2008, the American Association of Poison
Control Centers’ National Poison Data System (NPDS) reported
11,726 poisoning cases that involved hydrocodone alone,
26,166 poisoning cases that involved hydrocodone in combination with other drugs and 21 hydrocodone-associated deaths
(1). Hydrocodone is more potent than codeine (minimum
adult lethal dose 100 mg) and has a greater addiction liability
(2). Adverse or toxic effects of overdose include stupor, muscle
flaccidity, respiratory depression, hypotension and coma (2).
Hydrocodone is marketed as an extended release oral formulation and as a combination product with acetaminophen or ibuprofen. The combination products are classified as Schedule III
controlled substances.
After administration of hydrocodone, urinary excretion of
hydrocodone is 6 –20%, norhydrocodone 2 –14% and hydromorphone 5– 6% (3, 4). Other hydrocodone metabolites detected in
human urine include dihydrocodeine, isodihydrocodeine, dihydromorphone and isodihydromorphone (3, 4). Hydrocodone undergoes cytochrome P450- (CYP-) dependent oxidation to the
O- and N-demethylated products, thus forming hydromorphone
via CYP2D6 and norhydrocodone via CYP3A4 (5, 6). Genetic
polymorphisms exist for CYP2D6 and CYP3A4. Genetic polymorphisms of CYP2D6 result in a phenotypic classification ranging
from poor to ultra-extensive metabolizers (7). About 2 – 10% of
the population are homozygous for non-functional CYP2D6 mutant alleles resulting in a poor metabolizer phenotype (7).
Patients who are CYP2D6 poor metabolizers may experience variable hydrocodone side effects, efficacy and dependence (8, 9).
In contrast, conflicting data exist regarding the contribution of
CYP3A4 and CYP3A5 genetic polymorphisms on drug metabolism (10, 11).
Inter- and intrasubject variability of urinary hydrocodone has
been reported to be 134- and 23-fold, respectively (12).
Hydromorphone inter- and intrasubject variability is 51- and
27-fold, respectively (12). Numerous factors are known to influence inter- and intrasubject variability of hydrocodone and metabolites. Plasma concentrations of hydromorphone are higher in
men, whereas women have higher norhydrocodone plasma concentrations (13). Higher norhydrocodone concentrations may be
due to higher CYP3A4 density and/or activity in women (14).
Age and concurrent use with medications that are metabolized
by the CYP2D6 and/or CYP3A4 pathways may be additional contributory factors. The influence of these factors on hydrocodone,
hydromorphone and norhydrocodone concentrations has not
been extensively studied in urine. Understanding which factors
and the extent of such factors in influencing hydrocodone concentration variability is important in possibly explaining differential response patterns in patients. The purpose of this
retrospective data analysis was to evaluate the effects of sex,
age, urinary pH and concurrent use of CYP2D6 and CYP3A4 inhibitors on urinary hydrocodone, hydromorphone and norhydrocodone mole fractions.
Methods
Subject selection
Urine specimens were collected at pain physician practices from
patients on opioid therapy for routine drug monitoring purposes.
This study received Institutional Review Board exempt status by
the University of California, San Diego Human Research
Protection Program. Between January 2011 and August 2011,
517,775 random, de-identified urine specimens were collected
and analyzed by Millennium Laboratories (San Diego, CA, USA).
Inclusion criteria were specimens from a subject’s first or single
visit, subjects 16 years of age or older, detectable concentrations
(.50 ng/mL) of hydrocodone, hydromorphone and norhydrocodone analytes, and documented hydrocodone use via a medication list (e.g. physician-reported hydrocodone use). Exclusion
criteria were as follows: specimens with urine creatinine
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
concentrations of ,20 mg/dL, missing patient demographic data
(e.g. date of birth, sex), physician-reported hydromorphone, codeine and morphine use, as well as detectable concentrations
of morphine, codeine and heroin metabolite (6-monoacetylmorphine). Morphine, codeine and 6-monoacetylmorphine concentrations were detected via liquid chromatography–tandem mass
spectrometry (LC–MS-MS) with the lower limit of quantitation of
,50 ng/mL for each analyte. Subjects with urine creatinine concentrations of ,20 mg/dL were excluded because this indicated
a diluted specimen (15, 16). For the evaluation of CYP2D6 and
CYP3A4 inhibitor use, physician-reported CYP2D6 inducer
(n ¼ 14) use and physician-reported CYP3A4 inducer use
(n ¼ 1,629) were additional exclusion criteria.
Analytical procedure
Urinary concentrations were analyzed by LC–MS-MS (12, 17, 18).
In brief, an Agilent 1200 series binary pump SL LC system,
well-plate sampler and thermostatted column compartment
paired with an Agilent Triple Quadrupole Mass Spectrometer
and Agilent Mass Hunter software were used for the analysis of
hydrocodone, hydromorphone and norhydrocodone. Chromatographic separation was performed using an acetonitrile –formic
acid–water gradient running at 0.4 mL/min and a 2.1 50 mm2,
1.8-mm Zorbox SB C 18 column. Mobile phase A ¼ þ0.1 percent
formic acid in water, B ¼ 0.1 percent formic acid in acetonitrile
and column temperature was set to 508C. Samples were prepared
for injection by incubating 25 mL of urine with 50 Units of
b-Glucuronidase Type L-II (keyhole limpet) Sigma Product number G 8132 (Sigma-Aldrich Corp., Saint Louis, MO, USA) in 50 mL
of 0.4 M acetate buffer ( pH 4.5) for 3 h at 458C. Five microliters
of the solution was injected for each sample.
All spectra were collected using positive electrospray ionization. The optimized instrumental parameters were as follows:
gas temperature, 3508C; drying gas, 12 L/min; nebulizer gas
(nitrogen), 35 psi (24,100 Pa); capillary voltage, 3,000 V; and
fragmenter voltage, 60 V. Multiple reaction monitoring (MRM)
mode was used for quantitation. Scan time was set to 500 ms.
In the MRM mode, two transitions were used to identify and
quantitate a single compound. A quantitative transition was
used to calculate concentration based on the quantifier ion,
and a second transition was used to ensure accurate identification of the target compound based on the ratio of the qualifier
ion to the quantifier ion. The ion criteria were used for the qualitative identification with +20% of the average ion ratios for
calibrators.
HPLC grade water, acetonitrile, methanol and formic acid were
obtained from VWR (Westchester, PA, USA). Hydrocodone,
hydromorphone and normorphone were obtained from
Cerilliant Corp. (Round Rock, TX, USA). At the beginning of the
analysis, the internal standard solution contained 1,500 ng/mL of
deuterated standard and enzyme b-glucuronidase. About 100 mL
of this solution was added to 25 mL of patient’s sample. The final
concentration of the internal standard was 1,200 ng/mL.
A four-point calibration curve was created by using a linear fit
and forcing the line to go through the origin. Accepted accuracy
for calibrators was +20% of the target value, and the coefficient
of determination (R 2) was required to be 0.99 as verification of
linearity and goodness of fit. The lower limit of quantitation for
the hydrocodone, hydromorphone and norhydromorphone was
50 ng/mL. The upper limit of linearity for both the hydrocodone
and hydromorphone assays was 100,000 ng/mL. The inter-assay
coefficient of variation for all the analytes at the low and high
ends of the quantitation curve was ,10% based on the analysis
of .100 runs.
Data and statistical analysis
Specimens were creatinine normalized to mg/g creatinine to account for subject variability due to muscle mass and hydration
status (19). In order to compare the parent drug and metabolite
in urine, creatinine normalized data were converted into moles
(20). Mole fractions of hydrocodone, hydromorphone and norhydrocodone were then determined by multiplying the molecular
weight and dividing by 1,000 (20). Mole fractions were used for
data analysis purposes since there is less interindividual variability versus urine concentrations (20), and to determine whether
the proportions of each metabolite change with total exposure
or with concurrent use of CYP2D6 and/or CYP3A4 inhibitors.
For the age analysis, specimens were divided into three groups:
16 –39 years, 40 –64 years and 65 years and older (21). For the
evaluation of urinary pH, specimens were divided into three
groups: 3.7 – 6.8, 6.9 – 7.9 and 8 – 11. For the evaluation of
CYP2D6 and CYP3A4 inhibitor use, specimens were separated
based on physician-reported medication use. Specimens that
did not include CYP2D6 and CYP3A4 inhibitors represented
the control group. A list of known CYP2D6 and CYP3A4 inhibitors were obtained from the University of Indiana, School of
Medicine (22). The medication history for each individual was
evaluated for the listed 36 CYP2D6 inhibitors and 31 CYP3A4 inhibitors. Mole fractions based on the presence of CYP2D6 and/or
CYP3A4 inhibitor use were compared with mole fractions from
the control group.
Descriptive statistics were conducted with Microsoft Excel
2007 (Microsoft Corp., Redmond, WA, USA), and all statistical
analysis was completed with OriginPro v8.1 (OriginLab,
Northampton, MA, USA). Mole fractions were log-transformed
to achieve a normal distribution. Mole fractions are presented
as means and 95% confidence intervals (95% CI). A one-way
ANOVA and two-sample unpaired t-test were performed.
Statistical significance, with a Bonferroni adjustment due to multiple comparison testing, was set at P 0.005 (23).
Results
The sample population is summarized in Figure 1. A total of
76,924 subjects were positive for at least one or more analytes.
There were 1,145 specimens (1.5%) that were positive for only
hydrocodone, 388 (0.5%) specimens for hydromorphone and
2,614 (3.4%) specimens for norhydrocodone. There were
48,710 specimens positive for all the three analytes. Mean hydrocodone, hydromorphone and norhydrocodone mole fractions
(95% CI) were 0.39 (0.38 – 0.39), 0.12 (0.11 – 0.12) and 0.49
(0.48–0.49), respectively.
Sex analysis
Hydrocodone, hydromorphone and norhydrocodone mole fractions were compared between women (n ¼ 27,622) and men
Urinary Hydrocodone and Metabolites 405
Figure 1. Flow chart of specimen and subject selection.
(n ¼ 21,088). In men, mean hydrocodone, hydromorphone and
norhydrocodone mole fractions (95% CI) were 0.41 (0.40– 0.41),
0.13 (0.12 –0.13) and 0.46 (0.45 –0.46), respectively. In women,
mean hydrocodone, hydromorphone and norhydrocodone mole
fractions (95% CI) were 0.38 (0.37 – 0.38), 0.11 (0.1 – 0.11) and
0.52 (0.51 – 0.52), respectively. Hydromorphone mole fractions
were higher in men compared with women (P , 0.0001).
Norhydrocodone mole fractions were higher in women
(P , 0.0001).
Table I
Mean (95% CI) Hydrocodone, Hydromorphone and Norhydrocodone Mole Fractions Based on Age
Parameter
N
Mole fractions
Hydrocodone
16– 39 years
40– 64 years
65 years and older
9,774
30,743
7,426
Hydromorphone
a,b
0.36 (0.35 –0.36)
0.39 (0.38 –0.39)b
0.4 (0.4 –0.41)
Norhydrocodone
a,b
0.12 (0.12 –0.13)
0.11 (0.11 –0.12)b
0.11 (0.11 –0.12)
0.52 (0.51 –0.52)a,b
0.49 (0.48 –0.49)b
0.48 (0.47 –0.48)
a
P-value 0.005 compared with the 46- to 64-year age group.
P-value 0.005 compared with the 65-year and older age group.
b
Age and urinary pH analysis
Mean + SD age was 51 + 13 years. Data are summarized in
Table I. Significant differences in hydrocodone, hydromorphone
and norhydrocodone mole fractions were observed. Hydrocodone
mole fractions were highest in the 65-year and older age group
compared with the other age groups. The hydromorphone mole
fractions were similar across the evaluated age groups, whereas
norhydrocodone mole fractions were highest in the 16- to
39-year age group. There were 38,618, 7,685 and 2,407 specimens
with urine pH of 3.7–6.8 (acidic), 6.9–7.9 (neutral) and 8–11 (basic),
respectively (Table II). Hydromorphone and norhydrocodone mole
406 Barakat et al.
Table II
Mean (95% CI) Hydrocodone, Hydromorphone and Norhydrocodone Mole Fractions Based on
Urinary pH
Urinary pH
N
Mole fractions
Hydrocodone
Hydromorphone
Norhydrocodone
3.7 –6.8
6.9 –7.9
8 –11
38,618
7,685
2,407
0.41 (0.4 –0.41)a,b
0.31 (0.3 –0.31)b
0.3 (0.29 –0.3)
0.11 (0.1 –0.11)a,b
0.15 (0.14 –0.15)b
0.15 (0.15 –0.16)
0.48 (0.47 –0.48)a,b
0.54 (0.53 –0.54)b
0.54 (0.54 –0.55)
a
P-value 0.005 compared with the 6.9 –7.9 urinary pH group.
P-value 0.005 compared with the 8 –11 urinary pH group.
b
fractions were higher in the neutral and basic urinary pH groups
(Table II).
Concurrent hydrocodone and CYP2D6 and/or CYP3A4
inhibitor use
Subjects (n ¼ 21,177) lacking a physician-reported medication
that was a CYP2D6 and CYP3A4 inhibitor (control group) observed hydrocodone, hydromorphone and norhydrocodone
mean mole fractions of 0.39, 0.11 and 0.49, respectively. There
were 3,787 patients with a physician-reported CYP2D6 inhibitor
medication. The most commonly reported CYP2D6 inhibitors
were duloxetine (n ¼ 1,700), sertraline (n ¼ 723) and bupropion (n ¼ 503). There was no difference in hydrocodone mole
fractions between the CYP2D6 inhibitor group and the control
group. In contrast, hydromorphone and norhydrocodone mole
fractions were significantly different for the CYP2D6 inhibitor
group (Table III).
There were 497 patients with a physician-reported CYP3A4
inhibitor medication. The most commonly reported CYP3A4
inhibitors were verapamil (n ¼ 119) and diltiazem (n ¼ 69).
Hydrocodone, hydromorphone and norhydrocodone mean
mole fractions during concurrent use of a CYP3A4 inhibitor
were 0.46, 0.12 and 0.42, respectively. There was no difference
in hydromorphone mole fractions between the CYP3A4 inhibitor
group and the control group. In contrast, hydrocodone and
norhydrocodone mole fractions were significantly different for
the CYP3A4 inhibitor group (Table III). Upon dual inhibition
with a CYP2D6 and CYP3A4 inhibitor (n ¼ 3,819), hydrocodone
and norhydrocodone mole fractions increased, while hydromorphone decreased (P , 0.005; Table III).
Discussion
Prevalence of hydrocodone and metabolites in urine
This was a retrospective study evaluating hydrocodone, hydromorphone and norhydrocodone distributions in urine. There
were 48,710 specimens positive for all three analytes, indicating
that these subjects were taking hydrocodone. Comparisons of
the prevalence of all three analytes to other published studies
are difficult. One study reported 570 positive urine specimens
of hydrocodone, hydromorphone and norhydrocodone in a
chronic pain patient population (n ¼ 13,126) (24). Another
study reported 52 of 2,654 urine specimens that were positive
for hydrocodone, hydromorphone and norhydrocodone (25).
In the current study, norhydrocodone had the highest mean
mole fraction, followed by hydrocodone and hydromorphone.
These results are consistent with previous studies reporting
higher urine concentrations of norhydrocodone and lower concentrations of hydromorphone, compared with hydrocodone
(24, 25). Taken together, these results support the observation
that norhydrocodone is the major metabolite of hydrocodone.
Sex effects on hydrocodone and metabolites
Hydromorphone and norhydrocodone mole fractions were significantly different based on sex. Hydromorphone mole fractions
were higher in men, whereas norhydrocodone mole fractions
were higher in women (P , 0.0001). CYP3A4 activity has been
observed to be higher in female liver microsomes, whereas
CYP2D6 activity is higher in male liver microsomes. This may explain the observed differences in hydromorphone and norhydrocodone mole fractions observed in the current study and the
reported differences regarding opioid analgesia and side effect
profiles between men and women (26). However, it should be
noted that numerous mechanisms have been suggested to explain the observed sex differences and should not be discounted.
These include, but are not limited to, higher estrogen concentrations in women, the relationship between analgesic and antianalgesic properties, psychological factors and genetic influences
(26).
Age effects on hydrocodone and metabolites
Physiologic factors such as hepatic function, renal function, liver
mass and hepatic blood flow are known to decrease with age
(27). In the current study, hydrocodone mole fractions were
higher in the 65-year and older age group compared with the
16- to 39-year age group. This seems to suggest an age-related reduction in metabolic capacity of hydrocodone, such as decreased
CYP2D6 activity, since the extent of hydromorphone metabolite
formation was low. However, age-related changes due to decreased CYP2D6 and/or CYP3A4 activity may not be contributory factors as one study reported a lack of age-dependent changes
in CYP2D6 and CYP3A4 (28). Regardless of which physiologic
factor impacted hydrocodone and hydromorphone mole fractions, it is of practical value to closely monitor a patient’s response to opioid medication use. In the older adult, cognitive
function and functional mobility may be compromised, which
place these individuals at a higher fall risk.
Table III
Mean (95% CI) Hydrocodone, Hydromorphone and Norhydrocodone Mole Fractions and Inhibitors*
Condition
No CYP2D6 and CYP3A4 inhibitors (control group)
CYP2D6 inhibitor
CYP3A4 inhibitor
CYP2D6 and CYP3A4 inhibitors
N
Mole fractions
21,177
3,787
497
3,819
Hydrocodone
Hydromorphone
Norhydrocodone
0.39 (0.38 –0.39)
0.39 (0.38 –0.39)
Not significant
0.46 (0.44 –0.48)
P , 0.005
0.41 (0.39 –0.41)
P , 0.005
0.11 (0.11 –0.13)
0.08 (0.07 –0.08)
P , 0.005
0.12 (0.1 –0.13)
Not significant
0.07 (0.06 –0.07)
P , 0.005
0.49 (0.48 –0.49)
0.53 (0.52 –0.53)
P , 0.005
0.42 (0.41 –0.44)
P , 0.005
0.53 (0.51 –0.53)
P , 0.005
*P-values determined upon comparison with the control group.
Urinary Hydrocodone and Metabolites 407
Urinary pH effects on hydrocodone and metabolites
Data are limited describing the relationship between the amount
excreted of opioid and corresponding urinary pH. Methadone is
one example whereby excretion is urinary pH-dependent, while
the metabolite EDDP is not dependent on pH (29). A significant
difference in the excretion pattern of the parent drug and metabolites based on urinary pH was observed in this study (Table II).
The urine specimens used for the analysis had a variable pH
range. These results suggest a need to minimize urinary pH variations by several approaches, including, but not limited to, maintaining specimen integrity at the collection site and during
laboratory analysis (30).
Concurrent hydrocodone and CYP2D6 and/or CYP3A4 use
Interindividual variability of hydrocodone pharmacokinetics
and pharmacodynamics is due, in part, to CYP2D6- and
CYP3A4-mediated drug – drug interactions (5, 31). Concurrent
administration of a CYP2D6 inhibitor would be expected to
lower hydromorphone metabolite formation due to competition
for binding sites on the CYP2D6 enzyme between hydrocodone
and the CYP2D6 inhibitor. Our results are in agreement, as
hydromorphone mole fractions during concurrent use of a
CYP2D6 inhibitor were lower compared with the control group
(Table III). Norhydrocodone mole fractions were also higher
and suggest a compensatory metabolic pathway. Hydrocodone
mole fractions did not change during concurrent CYP2D6 inhibitor use. This may be due to the contribution of an alternative
metabolic pathway (i.e. ketoreduction) by which hydrocodol
epimers are formed (24).
Concurrent administration of a CYP3A4 inhibitor would be
expected to lower norhydrocodone metabolite formation due
to competition for binding sites on the CYP3A4 enzyme between
hydrocodone and the CYP3A4 inhibitor. Our results are in agreement, as norhydrocodone mole fractions during concurrent use
of a CYP3A4 inhibitor were lower compared with the control
group (Table III). A compensatory metabolic pathway would
also be anticipated and result in higher hydromorphone mole
fractions. However, this was not observed as there was no statistically significant difference in hydromorphone mole fractions
during concurrent CYP3A4 inhibitor use compared with the
control group (Table III). Rather, hydrocodone mole fractions
were higher in the CYP3A4 inhibitor group, which is likely due
to parent drug accumulation.
Dual CYP2D6 and CYP3A4 inhibitor use affected hydrocodone, hydromorphone and norhydrocodone mole fractions,
compared with the control group (Table III). Upon comparison
between CYP2D6 and CYP3A4 inhibitor use versus CYP2D6 inhibitor use, the extent of differences in hydrocodone, hydromorphone and norhydrocodone is similar (Table III). We speculate
that CYP2D6 inhibitor use plays a more prominent role in contributing to hydrocodone and metabolite mole fraction differences compared with CYP3A4 inhibitor use.
40 h for hydrocodone, hydromorphone and norhydrocodone, respectively (32). There may also be variation in the timing of
hydrocodone relative to CYP2D6 and/or CYP3A4 inhibitor administration. The extent of contribution of these factors impacting hydrocodone, hydromorphone and/or norhydrocodone
mole fractions is unknown. Another study limitation was the presumption of medication use from physician-reported medication
lists. Subjects may have been taking hydromorphone, morphine
and/or codeine with unreported use. Attempts to limit this confounding variable included exclusion of specimens with detectable concentrations of morphine and codeine. Additionally,
subjects who were taking hydrocodone may have been study exclusions on the basis of unreported use.
No data were available regarding a subject’s CYP2D6 and
CYP3A4 genotype and qualitative and/or quantitative analysis
of medications that were CYP2D6 and/or CYP3A4 inhibitors.
However, CYP2D6 and CYP3A4 genotyping of all patients prior
to starting an opioid is not routinely performed in clinical practice. Rather, CYP genotyping is generally performed on a reactive
basis, in an effort to possibly explain a challenging clinical scenario (e.g. excessive sedation with low starting dose and lack
of analgesia after escalating doses). Even with medications such
as antidepressants and tamoxifen, with known alterations based
on CYP2D6 genotype (33, 34), formal recommendations are
lacking to genotype all patients prior to initiating therapy. In addition, qualitative and/or quantitative analysis of all medications
listed on the physician-reported medication list is unlikely.
Conclusions
This was a retrospective study evaluating hydrocodone, hydromorphone and norhydrocodone distributions in urine. There
were 48,710 specimens that were positive for all the three analytes. Norhydrocodone had the highest mole fraction, followed
by hydrocodone and hydromorphone. Women had lower hydrocodone and hydromorphone, but higher norhydrocodone mole
fractions. Hydrocodone mole fractions were higher in the
65-year and older age group compared with the 16- to 39-year
age group. However, the extent of hydromorphone metabolite
formation was low. Hydrocodone and metabolites are affected
by urinary pH variations. Increased awareness of concurrent
hydrocodone and medications that are metabolized by CYP2D6
and/or CYP3A4 is recommended, in lieu of the observed differences in hydrocodone and metabolite mole fractions during
CYP2D6 and/or CYP3A4 inhibition. Research is underway examining the combination of these patient factors (age, sex and urinary pH), the extent of CYP2D6 and/or CYP3A4 inhibition, and
the specific medication that is a CYP2D6 and/or CYP3A4 inhibitor on affecting hydrocodone, hydromorphone and norhydrocodone mole fractions.
Acknowledgments
Study limitations
The current study lacked dosing administration of hydrocodone.
One study has suggested that peak urine concentrations occur
3 – 9 h after administration, with detection times of 28, 26 and
408 Barakat et al.
The authors acknowledge Amadeo J. Pesce, PhD, DABCC, for his
crucial guidance and support throughout the entirety of this
study. Urine specimens were tested and provided by Millennium
Laboratories. J.D.M. is a paid consultant of Millennium
Laboratories, Inc.
Funding
This work was supported in part by an educational grant provided by the University of California San Diego Skaggs School of
Pharmacy and Pharmaceutical Sciences from an unrestricted
gift from the Millennium Research Institute (to N.H.B.).
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