Surgery for Obesity and Related Diseases 13 (2017) 1869–1874

Original article
Morphine and metabolites plasma levels after administration of sustained
release morphine in Roux-en-Y gastric bypass subjects versus matched
control subjects
Lorry Hachon, Pharm.D.a,b, Rafael Reis, Pharm.D.a,c, Laurence Labat, Pharm.D., Ph.D.a,c,d,
Christine Poitou, M.D., Ph.D.e, Aude Jacob, Pharm.D., Ph.D.a,d,
Xavier Declèves, Pharm.D., Ph.D.a,c,d, Celia Lloret-Linares, M.D., Ph.D.a,b,f,*
a
Inserm U1144, Paris, France
b
Therapeutic Research Unit, Department of Internal Medicine, Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisière, Paris, France
c
Biologie du médicament et Toxicologie, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France
d
Université Paris Descartes, UMR-S 1144, Paris, France
e
Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Nutrition, Université Pierre et Marie Curie, Institut
cardiométabolisme et nutrition (ICAN), Paris, France
f
Université Paris Diderot, UMR-S 1144, Paris, France
Received April 27, 2017; accepted July 25, 2017

Abstract Background: Better knowledge of opioid pharmacology after Roux-en-Y gastric bypass (RYGB)
is required for optimizing their use in this growing population.
Objective: The aim of this case-controlled pharmacokinetic (PK) study was to compare morphine
and its glucuronidated metabolites (morphine-3-glucuronide and morphine-6-glucuronide) plasma
PKs between patients with RYGB and their controls.
Settings: University hospital, Lariboisière Hospital, Paris.
Methods: Thirty milligrams of morphine as a sustained-release formulation was orally adminis-
tered in 12 women who had undergone RYGB for at least 2 years (RYGB group) and in their
nonsurgical controls matched for sex, body mass index (±2 points), and age (±5 yr). Morphine,
morphine-3-glucuronide, and morphine-6-glucuronide plasma concentrations over a 12-hour period
were determined by a validated method using liquid chromatography mass spectrometry in tandem.
Drowsiness, respiratory rate, and oxygen saturation were monitored during the PK visit.
Results: Morphine oral area under the curve (for time 0–12 hr; 115.8 ± 108.0 nmol.hr/L and 86.9 ±
38.8 nmol.hr/L for RYGB group and control group, respectively, P ¼ .71), morphine at maximal
concentration, metabolites oral area under the curve (for time 0–12 hr), and other PK parameters were
similar between groups. After drug administration, mean drowsiness was superior in RYGB group.
Mean respiratory rate and oxygen saturation were similar in both groups.
Conclusion: No dose adjustment seems to be needed for sustained release morphine when pre-
scribed to RYGB patients. (Surg Obes Relat Dis 2017;13:1869–1874.) r 2017 American Society
for Metabolic and Bariatric Surgery. All rights reserved.

Keywords: Obesity; Pain; Opioids; Morphine; Bariatric surgery; Metabolic ratio; Glucuronides

C.L-L. received h7500 from APICIL study group for conducting the The Roux-en-Y gastric bypass (RYGB), a well-known
clinical study. option for obese patients to achieve and sustain weight loss,
*
Correspondence: Celia Lloret-Linares, M.D., Ph.D., Hôpital Lariboisière–
remains the most common procedure performed to date
Département de Médecine Interne A, 2 rue Ambroise Paré-75010
Paris, France. worldwide [1]. In parallel with the restrictive procedure
E-mail: celialloret@yahoo.fr reducing the volume of the stomach, bypassing the

http://dx.doi.org/10.1016/j.soard.2017.07.030
1550-7289/r 2017 American Society for Metabolic and Bariatric Surgery. All rights reserved.

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1870 L. Hachon et al. / Surgery for Obesity and Related Diseases 13 (2017) 1869–1874
duodenum and part of the jejunum has been shown to limit
the net area available for drug and nutrient gastrointestinal
absorption [2]. An anticipated complication of physiologic
and anatomic changes is that RYGB may influence phar-
macokinetic (PK) parameters [3,4], raising an important
concern: determining whether a drug regimen should be
modified in patients who have undergone RYGB surgery.
To date, no single unified model can predict these changes
for all marketed drugs, so a case-by-case approach should
be taken in which each drug stands as an individual entity
and is investigated as such [5–7]. Moreover, PK studies
after oral administration of drugs in sustained-release (SR)
oral formulations are lacking.
Opioids are among the most effective drugs for the
treatment of pain. Until recently, opioids were reserved for
the treatment of acute pain and cancer pain syndromes. In
most developed countries, the annual consumption of
morphine has increased at a substantial rate in recent years,
reflecting its use in the treatment of chronic, nonterminal
pain conditions [8,9]. Nevertheless, Raebel et al. [10]
showed that 77% of chronic opioid users before bariatric
surgery continued opioid use in the year after surgery, with
even a greater use postoperatively than preoperatively.
Morphine has a narrow therapeutic window and an impor-
tant interindividual variability in drug response and toxicity,
partly influenced by PK [11]. Morphine-3-glucuronide (M3
G) and morphine-6-glucuronide (M6 G) are the major
metabolites of morphine, produced by the uridine diphos-
phate glucuronosyl transferase 2 B7 enzyme [11]. Sixty
percent of an oral dose of morphine is glucuronidated into
M3 G and 6% to 10% into the active metabolite M6 G [11].
M6 G has a high affinity for Mu opioids receptors and thus
is largely responsible for pain-relieving effects and a key
determinant of morphine benefit-risk balance, while M3 G
has a poor affinity for Mu opioid receptor and does not have
any analgesic effects [12].
In a previous longitudinal study, we investigated mor-
phine PK parameters after oral administration of morphine
sulphate in immediate release (IR) formulation in patients
before and after RYGB surgery. We showed that RYGB and
the subsequent body mass index (BMI) reduction dramati-
cally increased the rate of morphine absorption and slightly
increased systemic morphine exposure [13]. These results
suggested that the dose of morphine sulphate as IR
formulation might be subdivided after RYGB to prevent
adverse events due to early and high morphine plasma peaks
[13]. However, the effective management of severe pain and
the morphine titration strategy require immediate and SR
morphine formulations. The aim of the present study was to
compare the morphine PK after a single oral administration
of morphine 30 mg in an SR formulation in post-RYGB
patients and in nonsurgical control patients. Secondary
objectives of this study were to identify any differences in
the PK of morphine glucuronides and in some morphine-
induced pharmacodynamic effects between groups.
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Methods
Study population
The present study was a case-controlled PK study
comparing the morphine plasma concentration over time
curve between 12 women who had undergone RYGB
almost 2 years earlier (RYGB case group) and 12 women
without history of obesity surgery and gut surgery (control
group), matched for BMI (±2 kg/m²) and age (±5 yr).
Case and control patients were 18 to 70 years old,
in good general health as determined by history, physical
examination, and standard biology (aspartate and alanine
aminotransferase, prothrombin rate, total and free bilirubin,
serum creatinine, cholesterol, and triglycerides). Patients
were excluded for the following reasons: (1) renal or
hepatic dysfunction, (2) untreated obstructive sleep apnea
syndrome, (3) treatment with sedative drugs, morphine,
or codeine, and (4) history of allergy to morphine or
opioids.
The 12 RYGB patients were recruited in the department
of Nutrition, Pitié-Salpêtrière Hospital, Paris, France. These
patients had undergone RYGB by the same surgical team
using the same laparoscopic technique [14]. The 10 control
patients were caregivers recruited in Lariboisière Hospital
(Paris, France), and 2 additional controls were recruited in
the Department of Nutrition. Recruitment approaches
included flyers, face-to-face contact, and word of mouth.
All patients gave their written informed consent. The
protocol “OBEMO 2 study” was approved by the Ethics
Committee of Paris, France (CPP Ile de France I) and
registered at the ClinicalTrials.gov website (EudraCT num-
ber 2014-004720-22, NCT02641301).
Oral morphine and glucuronides PK study
After inclusion, morphine and glucuronides PK study
was planned. At arrival, weight and percentage of fat mass
were assessed using the Tanita BC-420 MA leg-to-leg
Bioelectrical Impedance [15]. Patients fasted from 10 PM
the preceding evening to minimize the effect of food intake
on morphine PK in the morning. Fasting subject were given
a single oral dose of SR morphine sulphate 30 mg (Skenan
LP 30 mg, Ethypharm, Grand Quevilly, France) and a
standardized breakfast 3 hours after morphine administra-
tion. Over the 12 hours after the morphine dose (.5, 1, 1.5,
2, 2.5, 3, 4, 5, 6, 8, and 12 hr), 11 blood samples were
taken. Vital signs were monitored at baseline and at each
blood draw: systolic and diastolic blood pressure (mm Hg),
heart rate (beats/min), respiratory rate (breaths/min), blood
oxygen saturation (%), Glasgow score, as well as the
presence of any adverse events (dizziness [yes/no], head-
aches [yes/no], confusion [yes/no], vomiting [yes/no]). The
degree of drowsiness was also assessed with a numerical
rating scale as reported by patients, from 0 (did not feel
drowsy) to 10 (fast asleep).
 Sustained Release Morphine in RYGB Patients / Surgery for Obesity and Related Diseases 13 (2017) 1869–1874 1871

Morphine, M3 G, and M6 G quantification in plasma
Morphine and its major metabolites (M3 G and M6 G)
were analyzed in plasma by a validated method using liquid
chromatography mass spectrometry in tandem after solid
phase extraction as described previously [16]. Chromato-
graphic separations were performed on a liquid chromatog-
raphy system (Accela system, Thermo Fisher) with Hypersil
Gold (Thermo Fisher) C18 column (2.1 × 100 mm, 3 μm) at
a flow rate of .2 mL/min. The mobile phase consisted of
.1% (vol/vol) formic acid water and .1% (vol/vol) formic
acid acetonitrile with a gradient elution. Mass spectrometry
was carried out in electrospray positive ionization mode on
a TSQ Quantum Ultra system (Thermo Fisher). Selective
Reaction Monitoring transitions were 286.1→201.0 for
morphine (m/z), 462.1→285.9 for M3 G and M6 G,
289.1→201.0 for morphine-d3 (internal standard [IS]),
465.1→288.9 for M3 G-d3 (internal standard), and M6 G-
d3 (internal standard). Quantification methods were vali-
dated over the tested concentration ranges in urine and
plasma (.15–200 ng/mL for morphine and M6 G; .75–1000
ng/mL for M3 G). Intra- and interday precision was less
than 10%.
between RYGB and control patients for biological and
clinical characteristics, morphine, M3 G and M6 G PK,
respiratory rate, oxygen saturation, and drowsiness were
studied using a paired t test for normal distribution
(Shapiro-Wilk test) or Wilcoxon signed rank tests for
nonnormal distribution. The AUC0–12 hr of morphine, M3
G, and M6 G were log-transformed to avoid the possible
nonnormality of their distribution. A bilateral test was used
to compare means in both groups, and P o .05 was
considered significant. Analyses were performed using Stata
software, version 12.1 (StataCorp LP, College Station, TX).
Results
Study population
Participants in the RYGB group had undergone surgery
6.0 (3.8–9.9) years previously, resulting in a median BMI
loss of 13.5 (7.4–20.5) kg/m² and a weight loss of 35.6
(19.1–56.1) kg. The characteristics of both groups (RYGB
and control patients) are shown in Table 1. The clinical and
biological data were not statistically different between
groups, in particular for BMI and age.

PK analysis Morphine, M6 G, and M6 G pharmacokinetics between

RYGB and control groups
The plasma morphine, M3 G, and M6 G concentrations
versus time data obtained from each individual subject were All participants completed the PK visit, and 262 blood
submitted to a noncompartmental PK analysis using samples were quantified for the calculation of PK parame-
WinNonlin (version 5.1, Pharsight Corporation, Cary, NC). ters. Concentration-time profiles are shown in Fig. 1 and PK
The area under the plasma concentration–time curve parameters of morphine, M3 G, and M6 G, as well as
(AUC0–Clast) from time zero to the last quantified sampling morphine metabolic ratio are presented in Table 2. We
time point (Clast) at which plasma levels for the 3 compounds observed a high interindividual variability in morphine
of interest were adequately determined was calculated using and metabolite PK parameters. Differences in morphine
the linear-up and log-down trapezoidal rule. Morphine and AUC0–12 hr and morphine Cmax were not statistically
glucuronides plasma concentration elimination for most different between groups. Morphine metabolite AUC0–12 hr
patients did not reach a pure elimination at the Clast because
the absorption phase of sustained forms of morphine is a Table 1
slow process that could be not be completed 12 hours after Clinical and biological characteristics of the patients
oral administration. Thus, calculation of extrapolated AUC
RYGB group Control group
from the Clast to infinity (AUC0–infinity) for each compound n ¼ 12 n ¼ 12
using Clast divided by the terminal elimination half-life was
Age (yr) 48.5 (34–61) 46.5 (30–57)
not acceptable because it was superior to 20% in both
BMI (kg/m2) 31.0 (23.4–42.6) 30.3 (23.0–42.3)
groups. AUC0–infinity and the terminal half-life (t1/2) of all Fat mass (%) 39.2 (27.1–52.2) 38.9 (19.5–48.6)
compounds have thus not been reported in the PK parame- Fat mass (kg) 30.6 (16.7–58.2) 28.7 (11.0–57.0)
ters. Values for the maximum plasma concentration (Cmax) Creatinine (μM) 62.9 (49.0–79.0) 59.0 (54.0–76.0)
and time to Cmax (Tmax) were obtained directly from the Creatinine clearance* (mL/min) 104.0 (67.0–144.0) 98.6 (76.0–121.0)
Aspartate aminotransferase (UI/L) 21 (11–36) 22 (14–30)
observed individual plasma concentration–time courses. The
Alanine aminotransferase (UI/L) 20 (11–28) 18.5 (10–32)
molar metabolic ratio of both M3 G and M6 G was Total bilirubin 8.3 (4.0–17.0) 8.0 (5.0–15.9)
calculated by dividing the AUC0–12 of M3 G or M6 G by Triglycerides (mM) 0.71 (0.5–1.5) 0.91 (0.32–3.0)
that of morphine (expressed in nmol.hr/L).
RYGB ¼ Roux-en-Y gastric bypass; BMI ¼ body mass index.
Results are expressed as medians (minimum–maximum).
Statistics *
Modification of Diet in Renal Disease Study equation: simplified version
for men: 86 × (creatinine [μM] × .0113) − 1.154 × age − .203 (× 1.21 for
Quantitative data were described as medians (range) and patients of African origin; × .742 for women; × .95 if the determination of
qualitative data as frequencies and percentages. Differences creatinine is calibrated isotope dilution mass spectrometry).

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1872 L. Hachon et al. / Surgery for Obesity and Related Diseases 13 (2017) 1869–1874

headache (2/12; 16.7%), gastrointestinal pain (6/12; 50%),

and pruritus (1/12; 8.3%).
Table 3 shows the degree of drowsiness, respiratory rate,
and oxygen saturation during the PK study. The degree of
drowsiness during the PK study was higher in the RYGB
group than in the control group (Table 3, Fig. 2). Respira-
tory rate and oxygen saturation were similar between
groups.

Discussion
Fig. 1. Plasma pharmacokinetics of morphine, morphine-3-glucuronide, In this study, we show that the PK of morphine and its
and morphine-6-glucuronide after a single oral dose of 30 mg of sustained
metabolites after oral administration of morphine in SR
release morphine for the 12-matched Roux-en-Y gastric bypass and control
patients (data are expressed as mean ± standard error of the mean). formulation was very similar between participants who had
undergone RYGB and controls matched for sex, age, and
and Cmax and morphine metabolic ratio were not statistically BMI. A higher degree of drowsiness was observed in
different between groups. patients with RYGB compared with controls.
To date, most studies aiming to study drug PK in patients
with RYGB have been performed after the oral adminis-
Pharmacodynamic parameters and safety evaluation
tration of drugs in solid or liquid IR formulation [17].
No serious or unexpected adverse events occurred during Shorter Tmax and higher Cmax of drugs were almost
study visits. The occurrence of side effects was not constantly observed in patients with RYGB compared with
significantly different between groups. In the RYGB group, their own PK data before surgery or with nonsurgical
we observed drowsiness (100%), nausea (3/12; 25%), controls [3,18]. These studies evidenced an effect of the
dizziness (4/12; 33.3%), vomiting more than 2 hours after modified gastrointestinal tract anatomy on the rate of drug
drug administration (2/12; 16.7%), headache (6/12; 50%), absorption, affecting both Cmax and Tmax. Only 1 study
gastrointestinal pain (5/12; 41.7%), and pruritus (0%). In investigated the PK of a drug in SR formulation, metopro-
the control group, we observed drowsiness (12/12; 100%), lol, before and after surgery [19]. It showed no statistically
nausea (2/12; 16.7%), dizziness (0%), vomiting more significant difference in Cmax, Tmax, and AUC, suggesting
than 2 hours after drug administration (1/12; 8.3%), that RYGB affected neither the rate nor the extent of oral
absorption of this drug administered in SR formulation, in
agreement with the present study. SR formulations are
Table 2 designed to slowly release the active substance into the
Morphine and metabolites pharmacokinetics after the administration of
morphine in sustained release formulation in 12 women with Roux-en-Y
intestinal lumen, lowering the rate of oral absorption but
gastric bypass and their controls prolonging the absorption phase. In RYGB patients, the
reduced gastric pouch and the bypassed portion of the small
RYGB group Control group P value
n ¼ 12 n ¼ 12 intestine would affect neither the rate of dissolution into the
lumen nor the extent of oral absorption of morphine when
Morphine
given as an SR formulation.
AUC0–12 (nmol.hr/L) 66 (32–406) 80 (34–156) .71
Tmax (hr) 3.0 (1.5–5.0) 2.6 (1.4–6.0) - Conversely, RYGB increases the absorption rate of
Cmax (nM) 11 (7–67) 16 (4–29) .72 morphine, as we previously demonstrated using an IR
M3 G formulation of morphine [13]. In this earlier longitudinal
AUC0–12 (nmol.h/L) 2810 (2240–4420) 3110 (1680–4340) .64 study, 30 mg of morphine was administered by oral route in
Tmax (hr) 3.1 (3.0–4.1) 4.0 (3.1–6.0) -
30 obese patients before and after RYGB; we showed a
Cmax (nM) 391 (315–652) 469 (216–628) .55
M6 G significant increase in the rate of morphine absorption (Tmax
AUC0–12 (nmol.h/L) 569.9 (334.5–812.0) 579.6 (319–1060) .92 was 7.5-times lower and Cmax 3.3-times higher 6 months
Tmax (hr) 3.0 (2.0–4.0) 4.0 (2.6–6.0) - later) and morphine exposure (1.55-fold). Morphine glucur-
Cmax (nM) 86 (55–114) 93 (51–141) .64 onidation also decreased with weight loss, thus contributing
M3 G/morphine
to increase morphine exposure [20]. We identified both the
Ratio AUC0–12 38.8 (10.9 –70.7) 39.9 (20.5–76.9) .45
M6 G/morphine surgery and weight loss as factors explaining the change in
Ratio AUC0–12 7.9 (1.4–15.7) 6.5 (3.8–12.7) .62 morphine PK [13,20]. As a consequence, we recommended
subdividing morphine dosage in patients after RYGB to
RYBG ¼ Roux-en-Y gastric bypass; AUC ¼ area under the curve;
Tmax ¼ time to reach maximal concentration; Cmax ¼ maximal concentra- prevent morphine adverse events due to early and high
tion; M3 G ¼ morphine-3-glucuronide; M6 G ¼ morphine-6-glucuronide. morphine plasma peaks when administered in IR formula-
Results are presented as median (range). tion [11]. Conversely, the present study suggests that no

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Table 3
Pharmacodynamic parameters after the administration of morphine in sustained release formulation in 12 women with Roux-en-Y gastric bypass and their
controls
RYGB group n ¼ 12 Control group n ¼ 12 P value

Drowsiness (numerical rating scale)

Baseline score 0 (.0–7.0) .3 (.0–4.0) .35
NRS score(.5–12 hr) 4.5 (2.4–7.9) 1.3 (.1–6.1) .004
Respiratory Rate (breathes/min)
Baseline RR 15.0 (10.0–23.0) 16.0 (10.0–24.0) .34
RR(.5–12 hr) 13.7 (10.4–22.8) 15.8 (8.8–21.5) .74
Oxygen saturation (%)
Baseline oxygen saturation 99.0 (96.0–100.0) 98.0 (96.0–99.0) .09
Saturation(.5–12 hr) 98.3 (96.4–99.5) 97.9 (94.4–98.9) .16

RYGB ¼ Roux-en-Y gastric bypass; NRS score(.5–12 hr) ¼ mean of NRS score evaluated during the visit, after drug administration (from time .5–12 hr);
RR(.5–12 hr) ¼ mean of respiratory rate evaluated during the visit, after drug administration (from time .5–12 hr); Saturation(0.5–12 hr) ¼ mean of blood oxygen
saturation evaluated during the visit, after drug administration (from T .5–12 h).
Results are presented as median (range).

dose adaptation of morphine in SR formulation should be
anticipated in RYGB after surgery.
Here, morphine glucuronidation estimated by the molar
ratio of morphine glucuronides over morphine plasma AUC
was similar between the RYGB and control groups,
suggesting a limited role of the bypassed intestine in oral
morphine glucuronidation. Finally, in accordance with our
previous study showing an influence of BMI on glucur-
onidation, the morphine metabolic ratio was similar
between groups who were BMI matched [20].
Independently of differences in morphine PK, higher
drowsiness was observed in RYGB patients in comparison
with nonsurgical patients. Some hypotheses can be made:
(1) history of RYGB and dramatic weight loss may account
for a greater tiredness, although patients feel in better health
than before the surgery [21], (2) because control patients
were mainly recruited in the hospital where the investiga-
tions took place, reaching the clinical center may have been
easier for them compared with RYGB patients, and it may
represent a bias, (3) morbid obesity may be associated with
endogenous susceptibility to drowsiness induced by
opioids, even after weight loss. Further studies are required
to explore this susceptibility and to investigate its
implications for pain management. Such studies should
include more accurate morphine pharmacodynamics
measurements.
Minor limitations can be mentioned. The 12-hour PK
visit may be too short to determine morphine AUC0–infinity
in the case of SR formulations. However, our time-course
study design was sufficient to evidence the absence
of difference in morphine PK in both groups, at least
during the absorption phase. Here, we used the same design
used by most studies investigating drug PK between
RYGB and control patients, and we did not study the
differences in morphine PK between pre- and postoperative
periods as a longitudinal study might do. Our results
cannot be extrapolated to other morphine SR formulations.
Finally, one cannot draw conclusions on how PK
correlates with morphine PD, including therapeutic effects,
because the study was only designed to investigate mor-
phine PK.
Conclusion
With similar morphine and metabolite PK, no specific
adjustment in morphine dosage seems necessary in patients
with RYGB when prescribed in SR formulation. Based on
the results of our previous study and this one, we
recommend rapid titration with intravenous morphine rather
than oral IR morphine for determining morphine SR
optimal dosage for the management of severe pain in
patients with RYGB. Finally, follow-up of morphine
prescription must take into account the well-known intrinsic
variability in morphine PK and pharmacodynamics for
optimizing morphine requirement.

Disclosures
Fig. 2. Drowsiness after a single oral dose of 30 mg of sustained release
morphine for 12-matched Roux-en-Y gastric bypass and control patients The authors have no commercial associations that might
(data are expressed as mean ± standard error of the mean). be a conflict of interest in relation to this article.

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