Primary: To assess the effects of cholestasis on metabolism of five drugs, who are metabolized by 5 different CYP P450 isoforms.Secondary: To correlate the effect of cholestasis on drug metabolism with the effect of cholestasis on bile acid…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The difference in area under the plasma concentration versus time curve (AUC)
for each drug following the oral administration of the drug cocktail prior to
ERCP in patients with cholestasis (A1) in comparison with the control situation
2 weeks after successful drainage has been achieved (A2).
Secondary outcome
The correlation between changes in AUC of the drugs and changes in AUC of
postprandial bile acids before and after biliary drainage.
Background summary
Hepatic metabolism of drugs is modulated by endogenous and exogenous factors.
Experimental studies have demonstrated that bile acids influence the gene
expression and activity of regulatory enzymes of cytochrome P450, next to their
influence on bile acid metabolism itself. Patients with posthepatic cholestasis
represent an unique human model for the excessive hepatic exposure to bile
acids and their effects on hepatic metabolism of drugs and bile acids. After
successful internal biliary drainage, these patients represent a model for the
waning effect of these excessive bile acids. Therefore, we aim to assess the
effects of posthepatic cholestasis, before and after biliary drainage, on
hepatic drug and bile acid metabolism to elucidate the extent to which bile
acids influence hepatic drug metabolism in humans.
Study objective
Primary: To assess the effects of cholestasis on metabolism of five drugs, who
are metabolized by 5 different CYP P450 isoforms.
Secondary: To correlate the effect of cholestasis on drug metabolism with the
effect of cholestasis on bile acid metabolism
Study design
Prospective intervention study
Intervention
This study consists of two study days. Subjects will receive a single
administration of a drug cocktail prior to (A1) and 2 weeks after (A2)
successful biliary drainage by ERCP. The drug cocktail consists of 50 mg
caffeine, 5 mg warfarin, 20 mg omeprazol, 20 mg metoprolol and 0.015 mgkg-1
midazolam. Pharmockinetic (PK) blood samples will be taken at t= 0, 2, 11,5,
15, 29, 41.5, 60, 90,135, 173, 180 and 195 minutes and 3.5, 4, 5, 7, 9 and 24
hours after administration of the drugs
A few hours after the drug cocktail, subjects receive a standardized liquid
meal which contains 25% of daily recommended calories, after which some
additional blood samples will be taken to assess bile acids, glucose and
insulin.
Study burden and risks
The burden of this study includes two 12-hour hospital admissions after an
overnight fast and two intravenous administrations of the drug cocktail. Blood
samples will be drawn via a second intravenous catheter for pharmacokinetic
(PK) analysis, metabolic analysis, monitoring of laboratory parameters and for
pharmacogenetic analysis of liver enzymes. A total volume of 250 ml blood will
be obtained. The risks for patients are low, since the cocktail consists of
low, subclinical doses of drugs frequently used in daily clinical practice
without adverse events.
This study will generate information regarding the drug metabolizing activity
and bile acid metabolism during cholestasis and may therefore be of future
benefit for patients with cholestasis using medication.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
- Bilirubin > 50 mmol/l, caused by posthepatic biliary obstruction
- Endoscopic Retrograde CholangioPancreatography (ERCP) has been scheduled
- > 18 years old
Exclusion criteria
- Diabetes Mellitus (both type 1 and 2)
- Cholangitis
- If a significant change in use of medication after ERCP is to be expected
- Use of omeprazole, warfarin, metoprolol, caffeine or midazolam (= medication of our probe cocktail) as standard treatment
- Use of herbal medicine or medication that inhibits or induces CYP3A4/5, CYP2C9, CYP1A2, CYP2C19, CYP2D6
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 | NL44326.018.13 |