To assess the effect of short term starvation and short term high fat diet on orally administered acetaminophen metabolism in healthy subjects.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
farmacokinetiek van paracetamol, niet specifiek tbv een/meerdere aandoeningen
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint is the difference in area under the plasma concentration
versus time curve (AUC) for acetaminophen and six of its metabolites following
the administration of the medication after 36 hours of starvation or after
three days of a high fat diet in comparison with the control situation of an
overnight fast.
Secondary outcome
Secondary endpoints include the difference in the PK parameters clearance,
volume of distribution, absorption rate, mean residence time and elimination
half-life. Furthermore, the effect of short term starvation and high fat diet
in combination with APAP administration on glutathione metabolism will be
studied.
Background summary
Acetaminophen is one of the most widely used drugs. Although safe at a
therapeutic dose, an overdose can cause hepatotoxicity. Hepatotoxicity is
induced by formation of toxic metabolites by several enzyme systems in the
liver. The activity of many of these enzyme systems is modulated by nutritional
factors. Although hardly studied in humans, there are indications from
experimental studies that nutritional conditioning, i.e. the composition of the
previous nutrition, influences acetaminophen metabolism. Therefore, nutritional
conditioning may contribute to both inter- and intra-individual variations in
acetaminophen metabolism and hence in acetaminophen induced toxicity.
Study objective
To assess the effect of short term starvation and short term high fat diet on
orally administered acetaminophen metabolism in healthy subjects.
Study design
Open-label, single-dose crossover intervention study
Intervention
This study consists of three sequential interventions (n=9 subjects per
intervention). The order of the interventions is determined by random
assignment. Subjects will receive a single oral administration of 1000mg
acetaminophen (1) after an overnight fast (controls), (2) after 36h of
starvation or (3) a three day high fat diet.
Study burden and risks
The burden of this study includes a screening visit, three 8-hour hospital
admissions, an overnight fast, a period of 36 h of starvation, three days of a
high fat diet (a regular diet supplemented with 500ml of cream after supper)
and three administrations of 1000mg acetaminophen. One urine sample will be
taken to perform a urinary drug screening and during hospital admission 3x 8
hour urine will be collected to assess renal excretion of acetaminophen
metabolites. Subjects will keep a diary of their regular diet during three days
before the first hospital admission and will use the same diet in the three
days before the second and third intervention, with exception of the fasting
periods (overnight and 36h of starvation). Blood samples (36 samples of which
30 samples via an intravenous catheter) will be drawn for PK analysis (n=27),
monitoring of laboratory parameters (n=8) and for pharmacogenetic analysis of
CYP enzymes (n=1). A total volume of 121.5 ml blood will be obtained. The risks
for the healthy volunteers are low. This study will generate information
regarding the drug metabolizing activity of acetaminophen during fasting and
after a high fat diet and may therefore be of future benefit for patients with
differences in nutritional status using high dosed acetaminophen.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
- Healthy (determined by an experienced physician) male of 18 years or older at the time of signing the informed consent
- Normal renal and liver function
- capable of giving written informed consent and to comply with the requirements and restrictions listed in the informed consent form
Exclusion criteria
- Major illness in the past 3 months
- gastrointestinal disease which may influence drug absorption
-abnormalities in ASAT/ALAT/bilirubin/gammaGT/AF laboratory data
-drug abuse or alcoholism (>3 units of alcohol per day)
- participation in another clinical trial in the past 12 months
- difficulty in donating blood or limited accessibility of a vein
- use of tobacco products (induction liver enzymes)
- (chronic) use of medication
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL46677.018.13 |