Cyp3A4 metabolism before and after surgery induced weight loss in morbidly obese patients, using midazolam as a model drug

The prevalence of morbid obesity is rising worldwide1-2. Several general
physiologic alterations associated with obesity have been described in the
literature, however the impact of obesity on specific drug metabolic and
elimination pathways needs to be determined, particularly in view of the
ongoing increase in bodyweights worldwide.
Approximately 50% of all drugs are metabolised by the enzyme system CYP450
3A43, which predominantly occurs in the liver. Morbidly obese patient suffer
from low-grade inflammation4. The large lipid compartment consists of
adipocytes and macrophages that excrete many different adipokines and
inflammation factors, such as leptin, adiponectin, IL-6 and TNF-α5-7. In vitro
and animal studies have shown that inflammation factors, decrease cytochrome
p450 3A4 expression, following down regulation of CYP3A4 mediated
metabolism8-11. This phenomenon was confirmed in humans where critically ill
patients exhibit decreased CYP3A4 metabolism12-13.
Kotlyar and Carson (1999)14, reviewed studies comparing clearance parameters of
individual CYP3A4 mediated compounds in obese and control subject and
demonstrated a trend of lower CYP3A4 mediated clearance values in obese as
compared to non-obese individuals.
However, the studies summarized by Kotlyar and Carson (1999)14 only included
obese (BMI>30) and no morbidly obese patients (BMI>40). The influence of morbid
obesity (BMI>40), as seen in the clinic today, on CYP3A4 mediated clearance has
not been studied yet.
In addition to the liver, CYP3A4 enzymes are also located in the intestines
where they play a role in oral drug absorption. So far, no studies have
assessed the influence of weight on CYP3A4-mediated drug absorption.
In this study we hypothesize that a reduction in weight will increase CYP3A4
mediated metabolism in morbidly obese patients. To adequately test this
hypothesis we aim to assess CYP3A4 metabolism in morbidly obese patients using
midazolam as a (CYP3A4) model drug before weight reducing surgery and after the
significant loss of weight one year post surgery. In order to assess both oral
absorption and clearance, a semi-simultaneous administration design is applied.
This design will facilitate the quantification of the reduction of intestinal
and hepatic CYP3A4 metabolism and interpretation of its clinical relevance in
the morbidly obese population.

To compare midazolam pharmacokinetics in morbidly obese patients before/during
bariatric surgery and 0.5-2 year after surgery.

This is a prospective observational intervention study and will be performed
in morbidly obese patients before/during and 0.5-2 year after bariatric
surgery. At the day of surgery patients will receive both oral (7.5 mg) and
intravenous (5 mg) midazolam. Oral midazolam will be administered 2.5 hours
before surgery and the intravenous dose will be given at the induction of
anesthesia. Venous blood samples will be collected until 390 min post i.v.
midazolam dose.
As after 0.5-2 years patients will be at their weight loss optimum, patients
are invited to the hospital to participate in the second part of the study. A
similar schedule of oral and i.v. midazolam will be used and blood samples will
be drawn over the same time span (until 390 minutes after the i.v. midazolam
dose).

Oral and intravenous midazolam are frequently used as premedication or for
induction of anesthesia in routine clinical practise. The doses used in this
study protocol are considered low and are associated with minimal risk. This
study will take place during clinical practice (first visit) and outside
clinical practice (second visit). During the second visit, vital functions are
monitored by a physician.

Clinical practice (first visit)
During and after surgery a maximum amount of 75 millilitres of blood will be
sampled from an indwelling venous catheter (placed for clinical practice).

Second visit
For the second visit, patients will stay at the observatory for one day. Again
an oral and intravenous dose of midazolam will be administered and a maximum
amount of 75 millilitres of blood will be sampled from an indwelling venous
catheter before, placed for the purpose of this study.