Pharmacokinetics of intravenous acetaminophen and its metabolites in morbidly obese patients

Obesity represents one of the most important public health issues according to
the World Health Organization. Despite increased pharmacotherapy among obese
patients, there is a paucity of dosing guidelines for this population.
Pharmacokinetic (PK) and pharmacodynamic (PD) studies are necessary to
determine the appropriate dosing regimen as obese patients have a different
body composition compared to normal-weight individuals, which influences
especially the volume of distribution (Vd) and total clearance (Cl) of drugs
[1] [2].

Acetaminophen is a frequently used analgesic in the peri-operative setting.
Glucuronidation and sulphation are the main metabolic pathways; about 60% and
30% respectively [3] [4]. About 2% of acetaminophen is excreted unchanged in
the urine. Approximately 5 -10% of acetaminophen is metabolized by cytochrome
P450 to a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI) [4]. CYP2E1
is the primary enzyme responsible for the formation of this toxic compound in
humans [5] [6] [7]. NAPQI is immediately inactivated by conjugation with
glutathione to a neutral metabolite and excreted as cysteine and mercapturic
acid conjugates in urine [3].

Current literature consists of two studies in which the pharmacokinetics of
acetaminophen in obese adults are investigated [8-9]. The volume of
distribution (Vd) and clearance (Cl) are increased in obese patients in
comparison with control patients [9]. However none of these studies examined
the glucuronidation, sulphation and/ or oxidation (CYP2E1) pathway of
acetaminophen in obese patients. Because one of this pathways is involved in
acetaminophen toxicity, i.e. the CYP2E1 mediated pathway, it is important to
explore the separate contribution of these different metabolism pathways to
this increased clearance. Furthermore, these studies only examined the
pharmacokinetics of acetaminophen in moderately obese adults in stead of the
now frequently encountered morbidly obese adults.

In obesity glucuronidation is likely to be induced [10] [11]. Sulphation is not
examined in obese humans. The activity of CYP2E1 is higher in obese patients in
comparison with normal weight subjects [12] [13] [11] [14]. Liver fatty
infiltration (NAFLD, non alcoholic liver disease) and insulin resistance may be
the underlying cause of increased CYP2E1 activity in obese patients [11] [15].

Because of the possible higher Vd and higher Cl of acetaminophen in obese
patients, this group of patients may need a higher loading and maintenance
dose. However, the increased CYP2E1 pathway should be kept in consideration as
CYP2E1 catalyses the formation of NAPQI.
The formation of NAPQI has only been investigated in obese rats. The clearance
of the cysteine and mercapturic metabolites was increased by 56% after
administration of a subtoxic dose of acetaminophen (303 mg/kg ideal body
weight) [16]. This indicates an increase of the CYP2E1 pathway and formation of
the metabolite NAPQI. To place the 56% increase into perspective; the total
amount of CYP2E1 metabolism will be 7.5% in stead of the normal 5%. Also
gluthatione will be present to inactivate NAPQI.

This study will investigate the pharmacokinetics of acetaminophen (total Cl and
Vd) in morbidly obese patients. Specifically the different metabolic pathways
of acetaminophen in morbidly obese adults will be investigated;
glucuronidation, sulphation, CYP2E1 oxidation (measurable by cysteine and
mercapturic metabolites) and unchanged acetaminophen. This will be compared
with normal weight subjects, but also with the same patient group 0.5 - 2 years
post surgery to determine whether the changes induced by obesity will be
reversible after weight loss.

Primary objective:
- To study the pharmacokinetics of acetaminophen and metabolites in morbidly
obese patients and compare with normal weight patients.

Secondary objectives:
- To compare the pharmacokinetics of acetaminophen and metabolites in morbidly
obese patients at the time of bariatric surgery and 0.5 * 2 year after
bariatric surgery.
- To compare the safety of acetaminophen in morbidly obese patients with
normal weight patients.
- Assess the influence of both demographic (age, sex) and physiologic
covariates (body weight, insulin resistance, lipid levels and inflammation
markers) on acetaminophen pharmacokinetics.
- To evaluate the metabolomic profile in morbidly obese patients and normal
weight patients.

This is a prospective observational intervention study which will be performed
in morbidly obese patients around bariatric surgery. A control group consisting
of normal weight patients undergoing general surgery will also be included.
According to study protocol patients of both study groups will receive an
intravenous dose (2 g) of acetaminophen 45 minutes before surgery. Venous blood
samples will be collected until 480 minutes after intravenous acetaminophen
administration. In addition, 24 hour urine will be collected for both study
groups. Samples for liver function tests will be withdrawn at 24 hours for
these two groups and because blood withdrawal is already taking place at this
time point, one last blood sample will be taken for acetaminophen as well.

As after 0.5 * 2 years the bariatric patients will be at their weight loss
optimum, these patients are invited to the hospital to participate in the
second study visit. At the second study visit intravenous acetaminophen (2 g)
will be administered and blood samples will be collected until 480 minutes. In
addition, urine will be collected during the second study day.

There are no direct benefits of this study for the study patients. The results
of the study will provide insight into different metabolic and elimination
pathways of acetaminophen in morbidly obese patients. The potential risks
associated with this study are minimal as we are using a drug that is part of
our standard of care.
The dose which is used in this study is 2 g intravenous acetaminophen. Standard
of care is 1 g acetaminophen orally before surgery. The reason for choosing a
higher dose than standard of care is because of the quantification of the
cysteine and mercapturic metabolite with the HPLC assay. Multiple studies show
that a 2 g loading dose of intravenous acetaminophen is safe and effective [17]
[18] [19]. Maximum plasma concentrations reached were far below the threshold
for hepatotoxicity (150 *g/mL) and no hepatic adverse effects were measured
within 48 hours of 2 g acetaminophen treatment [17]. In addition, the SPC text
of acetaminophen reports that the toxic amount of acetaminophen administered as
a single dose is 7.5 g. Moreover, Juhl et al showed that the analgesic efficacy
of 2 g starting dose of intravenous acetaminophen is superior to recommended
dose of 1 g in terms of magnitude and duration of analgesic effect for
postoperative pain [18].
Furthermore increasing the dose of acetaminophen to 2 g allows for an extension
in the dosing interval to 8 hours in stead of the normal dosing interval of 6
hours. The extension in dosing interval allows us to study for the
pharmacokinetics of acetaminophen and metabolites, up to the 8 hours after
dosing. After 8 hours of blood sampling the standard postoperative pain
management procedure of acetaminophen will start (every 6 hours 1 g of
acetaminophen).
A maximum amount of 76 millilitres of blood will be sampled from an indwelling
venous catheter before, during and after surgery and one venipuncture at t = 24
hours. The catheter will be placed in addition to a regular intravenous
catheter used for standard clinical care. The sampling of blood will have no
influence on patient recovery.

The first study visit will take place around the bariatric surgery. For the
second study visit the bariatric patients need to come back to the hospital,
but this study visit can be combined with a routine post-operative follow up
visit in the out-patient clinic. A second acetaminophen pharmacokinetic profile
in the same individual after weight loss is essential to assess whether changes
between morbidly obese patients and normal weight patients are reversible upon
weight loss.