CYP3A4 Induction
Conditions
Keywords
4beta-OHcholesterol, Midazolam, CYP3A4, Enzyme induction, Drug metabolism
Brief summary
The objectives of this study are: * To investigate if the endogenous cholesterol metabolite, 4beta-OHcholesterol could be used as a marker for induction of cytochrome P450 (CYP) 3A4. * To compare 4beta-OHcholesterol with midazolam as a marker for induction of CYP3A4.
Interventions
DRUGRifampicin treatment
induction of CYP3A4 with one of three rifampicin doses (10, 20, 100 mg QD)
Sponsors
AstraZeneca
Karolinska University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Females and males. 2. Age of 18 and above. 3. Caucasians. 4. Healthy as assessed by medical history and examination by principal investigator or delegated personnel. 5. Accept to refrain from herbal drugs, natural preparations, and grapefruit juice 48 hours before and during the study period. 6. Accept to completely refrain from alcohol during day -1 to 1 and R14-R16. During the rest of the study moderate alcohol use is permitted (equal to 1 glass of wine or 1 beer per day). 7. Women of childbearing age should accept using a reliable barrier contraceptive method throughout the study. 8. Women of childbearing age should have a negative pregnancy test at the screening visit. 9. Capable of following given instructions. 10. Has given written informed consent after receiving both oral and written study information.
Exclusion criteria
1. Predisposal to allergic drug reactions. 2. Anamnestic and/or visual signs of infection. 3. Women are not allowed to use oral hormone-based contraceptives 2 weeks before start of study and during the study. 4. Participation in another study within one month before entering the present study. 5. Intake of any other drug that can influence the enzyme activity of CYP3A4. 6. Pregnancy. 7. Breast-feeding. 8. A history of liver disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 4beta-OHcholesterol | Directly before treatment with rifampicin and 14 days after the end of treatment with rifampicin | The primary objective of the study is to investigate whether the endogenous cholesterol metabolite 4β-hydroxycholesterol could be used as a marker for induction of CYP3A4. For this purpose the induction of 4β-hydroxycholesterol formation will be compared to the induction of quinine and midazolam metabolism. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ratio between midazolam AUC induced and midazolam AUC uninduced | Before treatment with rifampicin and after 14 days of treatment with rifampicin | Secondary aim of the study is to compare 4β-hydroxycholesterol as a biomarker for CYP3A4 compared to 6β-hydroxycortisol/cortisol ratio, which sometimes is used as a marker for CYP3A4 induction. Another secondary aim is to relate our estimations of CYP3A4-expression to measured levels of 25-OH-vitamin D. |
Countries
Sweden
Outcome results
None listed