The effect of Roux-en-Y gastric bypass on the rate and extent of absorption of metoprolol from a controlled release tablet in female bariatric patient volunteers: a single oral dose study before and after surgery

Obesity is a growing world wide problem. In The Netherlands, about 10% of all
men and women have a BMI of 30 kg/m2 or more. Obesity is a chronic, uncurable
metabolic disorder, which is characterised by excessive fatstorage at
unfavorable places. Obese people have a higher risk to develop comorbidities
like diabetes mellitus II, cardio vascular diseases and osteoarthritis. Morbid
obesity, a BMI >= 40 kg/m2, is also associated with reduced life expectancy.
Bariatric surgery is an operation for obese people with a BMI >= 40 kg/m2 or >35
kg/m2 with a comorbidity, who are not able to lose weight by themself. The
number of patients undergoing bariatric surgery is rapidly increasing. Several
metabolic operations can be divided into a restrictive (gastric band, sleeve
gastrectomy), a malabsorptive (biliopancreatic deviation) and a combined
restrictive/malabsorptive (gastric bypass) procedure. In The Netherlands the
Roux-en-Y gastric bypass is the most frequently performed operation, with the
best long term results. Bariatric surgery has been shown to lead to sustained
weight loss, resolution of comorbidities and improved life expectancy.
Theoretically, bariatric surgery may alter the pharmacokinetics of orally taken
drugs. Depending on the type of operation, different factors might influence
drug absorption. A gastric restriction has influence at gastric mixing, gastric
pH and gastric emptying. These changes may influence drug absorption by an
altered drug disintegration and dissolution. Secondly, because of the reduced
functional gastrointestinal length after a bypass procedure the absorption of
drugs across the duodenum and jejunum might be reduced. This might be
counterbalanced by *intestinal adaptation*, whereby mucosal hypertrophy within
the remaining intestine results in an increased absorptive capacity.
Altered drug absorption will be a problem especially for oral formulations with
a coating or with a modified release profile. These technological formulations
are developed to disintegrate at a higher pH, or to dissolute slowly. In the
USA investigators advocate that formulations with controlled release should not
be used after bariatric surgery. However this is based on theoretical aspects
and not on clinical studies.
The absorption of lipophilic drugs might be decreased because bile salts may
emulsify the lipophilic drugs for absorption much later. Results showed that
after a partial gastric resection the absorption of the lipophilic β-blocker
propranolol is significantly decreased compared to the hydrophilic β-blocker
atenolol. Although bariatric surgery may theoretically have effect on the
pharmacokinetics of drugs, there is little known about the pharmacokinetics of
drugs after bariatric surgery. In this study we want to investigate the
pharmacokinetic profile of a controlled release lipophilic drug before and
after a Roux-en-Y gastric bypass.
Preliminary results of a retrospective study show that metoprolol belongs to
the top 15 of most used drugs by bariatric surgery patients. The majority of
these patients use metoprolol as a controlled release formulation. For these
reasons metoprolol CR will be used in this study. However another
pharmacokinetic study with metoprolol immediate release will also be performed.
To determine the effect of the Roux-en-Y gastric bypass, the rate and extent of
absorption of metoprolol CR before and after this surgery will be compared. In
this study, the patient is his own control.

To investigate the effect of Roux-en-Y gastric bypass on the rate and extent of
absorption of metoprolol and its main active metabolite α-OH metoprolol, after
a single oral dose of 95 mg metoprolol CR tablet in 10 female bariatric surgery
patient volunteers, before and after surgery.


The pharmacokinetic parameters that will be determined are:
- Cmax The maximum serum concentration of metoprolol.
- Tmax The time after oral administration of metoprolol when the
maximum serum concentration is reached.
- AUC t=0-24 The area under the serum concentration-time curve, a measurement
of the bioavailability of metoprolol until 24 hours after intake.

The effect can be determined according to the following ratios as listed in the
studyprotocol.

A single dose, fasting, explorative pharmacokinetic study before and after
surgery, with the patient as his own control.

This study concerns an explorative two-phase single oral dose pharmacokinetic
study of metoprolol under fasting conditions in patients undergoing bariatric
surgery. The single dose will be administered twice in each patient, once
before and once after bariatric surgery.

The study will be performed in 2013-2014.

The study takes place at the clinical research unit of the MCL. Analysis of the
samples will take place in the Laboratory for Drug Analysis and Clinical
Toxicology of the Department of Clinical Pharmacy and Clinical Pharmacology MCL.

Details
- A total of 10 female bariatric surgery patient volunteers will participate in
this study.
- The study is divided into two periods. One period before scheduled surgery
and one after surgery.
- Metoprolol succinate 95 mg controlled release tablet will be used.
- The patient will stay at the MCL for 10 hours.
- Each visit, a total of 10 blood samples of 5 ml will be collected
- 24 hours after the intake of the tablet a blood sample of 5 ml will be
collected at the patient*s home
- Blood pressure and heart rate will be monitored.
- Four months after surgery before the start of the second phase of the study
the patient will be asked about dumping syndrome symptoms by means of a
questionnaire. Dumping syndrome is characterized by symptoms of nausea,
shaking, sweating, diarrhea, light-headedness, flushing, tachycardia (fast
heart rate) and possibly fainting shortly after eating foods containing high
amounts of refined sugars and when eating too fast. Side effects of metoprolol
might resemble these symptoms. If the patient is suffering from the dumping
syndrome, the patient will be withdrawn from the study.

One month before and six months after Roux-en-Y gastric bypass the patient
takes a single oral dose of 95 mg of metoprolol CR tablet.

There will be no direct benefit for included patients. After having given
written informed consent to participate in the study, the patient is required
to undergo a medical examination. The patient has to visit the MCL for two
days. The first visit is scheduled one month before the surgery and the second
visit six months after surgery. The procedure of both visits is the same. A
single dose of 95 mg of metoprolol may cause side effects like hypotension,
headache and dizziness, but these side effects are moderate. Blood pressure and
heart rate will be monitored regularly. The patient is not allowed to lie down
during the first six hours of the study. During each phase, 11 blood samples of
5 ml each will be collected according to a time schedule by a venous cannula.
An intensivist is available for questions and safety of the patient. The
patient has to stay at the clinical research unit, but is not confined to bed.