Pharmacokinetics of Paracetamol before and after Roux-en-Y gastric bypass

The number of bariatric procedures performed in the Netherlands is increasing,
especially the Roux-en-Y gastric bypass (RYGB). Little is known about the
effect of RYGB on the pharmacokinetics of drugs. First of all, the absorption
of drugs could be altered in a reversible or irreversible way. Secondly, the
body composition will change after surgery which could further influence the
pharmacokinetics. In the period after RYGB, the effect on the pharmacokinetics
of a drug may gradually change.

In morbidly obese people, pharmacokinetics of paracetamol (PCM) is different
compared to healthy non-obese volunteers. The peak concentration (Cmax) of and
total exposure (AUC, area under the plasma concentration versus time curve) to
PCM are lower in morbidly obese people. The metabolism of PCM was shown to be
increased with higher activity of glucuronidation, sulfatation and
CYP2E1-mediated metabolism, resulting in higher concentrations of paracetamol
glucuronide (PCM-GLU), paracetamol sulfate (PCM-SUL), paracetamol mercapturate
(PCM-MER) and paracetamol cysteine (PCM-CYS). This effect was demonstrated
after administration of a single dose of 2 g PCM.

A pharmacokinetic study in RYGB patients showed that the absorption of PCM was
faster and that Cmax and AUC increased to values that are comparable to
non-obese patients. An important limitation of this study is that the dose used
was a single dose of 500 mg PCM, whereas the usual dose of PCM in the
Netherlands is 1000 mg per dose.

To assess the effect of a Roux-en-Y gastric bypass on the pharmacokinetics of a
single oral dose of 1000 mg paracetamol

This study is an open-label, longitudinal pharmacokinetic study. 20 morbidly
obese patients will be included, who are planned to undergo a Roux-en-Y gastric
bypass surgery. Pharmacokinetics of a single oral dose of 1000 mg paracetamol
(PCM) will be assessed at 3 time points: up to 2 months before RYGB, and at 2-6
weeks and 5-7 months after surgery.

The moments for pharmacokinetic sampling will be combined with regular visits
of the patients to the hospital to avoid unnecessary burden for the patients.
Furthermore, eight healthy non-obese volunteers will be included to assess the
pharmacokinetics of a single oral dose of 1000 mg PCM.

All participants will be screened and asked for informed consent.

In this prospective study, pharmacokinetics of a single oral dose of 1000 mg
paracetamol (PCM) will be assessed at three time points: once before and twice
after RYGB. Pharmacokinetics of a single oral dose of 1000 mg PCM will be
assessed once in healthy volunteers.

For this study, patients will be asked to extend their stay in the hospital on
visit days to at least 6 hours. At 8 time points, blood samples will be drawn.
To minimize burden for patients, they will receive a venflon allowing multiple
blood sampling via the same venepuncture. Moreover, visits of patients will be
combined with regular visits of participants, so that they do not need to come
to the hospital for an extra time. Blood sampling will be done by trained
personnel. Thus, risks during withdrawal of blood are minimized as much as
possible.

The outcomes of this study are important to assess to what extent
pharmacokinetics of PCM will change after RYGB. This could have consequences
for the advised PCM dosing for patients after RYGB, especially since
paracetamol is a freely available over the counter drug. Moreover, paracetamol
is a first choice drug to treat pain and fever. If the exposure to PCM after
RYGB is lower, higher dosages could be justified in case of inadequate pain
control. However, this must not lead to higher exposure to toxic metabolites of
PCM.

Participants need to stay at least 6 hours in the hospital. There are 8 time
points to withdraw blood of the participants. In this study, burden for
participants is minimalized. Participants receive a venflon. As a result of
this, multiple blood sampling can take place via the same venapunction.