The effect of Roux-en-Y gastric bypass surgery in morbidly obese patients on Pharmacokinetics of (Acetyl)salicylic acid and Omeprazole.

Roux-en-Y Bariatric (RYGB) surgery is a successful approach to morbid obesity.
In this procedure, the stomach is reduced to a small 'gastric pouch' . The
duodenum is bypassed by connecting the jejunum this gastric pouch. The duodenum
is then connected to a later part of the jejunum to ensure the passage of bile
salts and pancreatic enzymes.

After oral intake, food and drugs first pass the created gastric pouch before
passing directly into the shortened jejunum. Literature shows that this results
in problems regarding vitamin and nutrient absorption. In contrast, little
literature is available on the absorption of orally administered drugs. The
available literature consists mainly of case reports or small studies. Several
authors have tried to build a model in which the change in absorption after
RYGB surgery can be predicted, unfortunately without success. As there is no
model available for predicting changes in drug absorption after the surgery,
research is necessary for drugs frequently used in this population. We
investigated the medication use of 115 patients in our center to obtain insight
into the types of medication frequently used by this group of patients. Results
showed that aspirin and omeprazole are two commonly used drugs.

In order to prevent arterial thrombotic disease in high-risk patients such as
our population, treatment with acetylsalicylic acid is commonly prescribed for
life-long use. A dosage of 75-150 mg is proven to be an efficient dose in
preventing mortality, myocardial infarction or stroke. This is not proven for a
dose of less than 75 mg per day, except for stroke.
Acetylsalicylic acid is mainly absorbed in the acidic environment of the
stomach and partly in the duodenum. Changes in pH and gastric volume after RYGB
surgery could affect the extent of absorption of ASA. Until now, no data are
available on absorption of ASA in RYGB surgery patients. Reduced absorption of
aspirin could have long term implications for the effectiveness in the
prevention of thromboembolic events and death. For this reason, it is important
to investigate the impact of RYGB on the absorption of acetylsalicylic acid.
We hypothesize that the absorption of acetylsalicylic acid after oral
administration will be reduced by RYGB surgery.

As a proton pump inhibitor, omeprazole inhibits the production of stomach acid,
resulting in a less acidic stomach. Omeprazole is prescribed after RYGB
operation in a dosage of 20 mg twice daily to reduce the chance of development
of anastomotic ulcerations and leakage.
Omeprazole is an acid labile substance and is therefore always administered
with an enteric coating. After passing the stomach this coating dissolves and
omeprazole is rapidly absorbed in the small intestine. Due to a higher pH in
the stomach after RYGB surgery, the enteric coating around the tablet can
disappear faster and omeprazole could be more rapidly absorbed. An in vitro
experiment indeed showed an accelerated uptake of omeprazole after the
procedure, with no effect on the overall absorption of omeprazole. It is of
great importance that the absorption of omeprazole is sufficient to prevent
complications after RYGB surgery. For this reason we want to confirm previous
results and investigate the influence of RYGB surgery on the absorption of
omeprazole in this study
We hypothesize that the absorption of omeprazole after oral administration will
be faster but equivalent after RYGB surgery.

The primary objective of the ERY-PAO study is to investigate the
pharmacokinetics of acetylsalicylic acid (ASA) and omeprazole in morbidly obese
subjects before and after RYGB surgery and to compare these data to study if
there are differences in pharmacokinetics due to this procedure.

Single centre, longitudinal open label repeated measures study.

The subjects will be asked to take omeprazole 20 mg for a total duration of 2
weeks (day 1 - 14) before the RYGB surgery. After surgery, administration of
omeprazole 20 mg twice daily is standard care for the duration of 6 months. In
addition, the subjects will be asked to take a single dose of ASA 80 mg on 2
*test* days: day 7 of omeprazole treatment before surgery, and day 7 of study
medication omeprazole treatment after RYGB surgery. Test days will be planned
at least 2 weeks before and 6 weeks after the surgery. During the intervention
periods, the subjects will be asked to fill out a medication diary to check
adherence.

The medicinal intervention will gain no direct benefit for the study subjects.
However, the results of the study will definitely be beneficial to the study
subjects. Available information on oral absorption of medication after RYGB
surgery is limited. Most study subjects will be relatively young, but already
eligible to use multiple drugs. When they get older even more medicines,
possibly including ASA and omeprazole, will be prescribed to patients who
underwent RYGB surgery.
Any information about the oral uptake of drugs can provide new insights on how
to treat these patients in a safe and effective way. For omeprazole,
administration during 6 months is standard care for the study subjects. The
results of the ERY-PAO study will determine whether this standard care is
sufficient and, if necessary, standard protocols can be adapted for future
patients.

ASA has been used in clinical practice since 1899. The most important side
effect of low dose ASA is stomach ache. Complications can include
gastro-intestinal bleeding or ulceration. The absolute risk of upper
gastro-intestinal complications in low dose ASA use is approximately 2 to 3 per
1000 person-years (51). The relative risk of high gastro-intestinal bleeding in
low dose ASA use varies between 1,4 and 5,3 (52). In order to prevent these
complications, co-administration of a proton pump inhibitor is recommended
(52;53). This reduces the relative risk for gastro- intestinal bleeding in low
dose ASA users from 3,8 [2,8-5,2] to 1,1 [0,5-2,6]. In the ERY-PAO study, 2
single doses of ASA will be administered in combination with a proton pump
inhibitor. Hence, for our subjects, there will be no extra risk of stomach
complications.

Another potential risk for ASA use is a prolonged bleeding time. This effect
will continue during the life time of the thrombocyte, so one week after
discontinuation of ASA 90% of the thrombocytes will have normal function (55).
Hence, it is recommended to discontinue use of ASA a week before some surgeries
(56). In cardiac patients undergoing RYGB surgery, continuation of ASA 80 mg
proved to be safe for use until the day of the surgery (57). In the ERY-PAO
study, administration of a single dose of ASA will be given at least two weeks
before the RYGB surgery and at least 6 weeks after the surgery to rule out a
prolonged bleeding time due to ASA during surgery.

For omeprazole, no serious side effects have been described since the regular
use of this drug in clinical practice (since 1988). Common side effects include
nausea, flatulence and diarrhea