HealthyNCT00162474
Determinants of Warfarin Metabolism
A study testing Warfarin, Phenytoin and Losartan & Hydrochlorothiazide in people with Healthy, run by Hadassah Medical Organization at 1 site in Israel.
Trial summary
The anticoagulant effect of warfarin varies greatly among individuals. Some of this variability is attributed to differences in the activity of CYP2C9, the predominant enzyme involved in the metabolism of S-warfarin. Read more about this study
- Who is it for?
- Ages 20 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- Warfarin, Phenytoin and Losartan & Hydrochlorothiazide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 1,000 participants
- Where
- 1 siteIsrael
- Study dates
- Sep 2003to Dec 2030
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- Age range of 20-50 years old
- The absence of significant disease states
Who cannot join
- Known hypersensitivity to warfarin or phenytoin
- Known hepersensitivity to penicillins or cephalosporins (Dicloxacillin part)
- The presence of significant disease states
- Regular use of drugs (including birth control pills)
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Israel1 site, 1 recruiting
- Recruiting
Hadassah Medical Organization
Jerusalem
Arik Tzukert, DMD, 00 972 2 6776095, arik@hadassah.org.il
Hadas Lemberg, PhD, 00 972 2 6777572, lhadas@hadassah.org.il
About this study
Official title: Correlation Between Phenotypic Activity of CYP2C9 and Genetic Polymorphism in CYP2C9 and Warfarin Metabolism.
The anticoagulant effect of warfarin varies greatly among individuals. Some of this variability is attributed to differences in the activity of CYP2C9, the predominant enzyme involved in the metabolism of S-warfarin.
The present study is designed to define the differences in warfarin metabolism among healthy individuals carrying different CYP2C9 genotypes. In addition, the study will define the correlation between the phenytoin metabolic ratio, a marker of CYP2C9 activity in vivo, and warfarin metabolism.
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WarfarinDrug
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
PhenytoinDrug
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Losartan & HydrochlorothiazideDrug
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
FlurbiprofenDrug
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
SiponimodDrug
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
DicloxacillinDrug
To explore possible effect of dicloxacillin on CYP2C9 activity, some participants will be administered single dose of warfarin and phenytoin before and after intake of dicloxacillin.
| Study group | Role | What they receive |
|---|---|---|
| CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. | Experimental | Each participant may be given at least one of the following CYP2C9 substrates: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. Receives: Drug: Warfarin; Drug: Phenytoin; Drug: Losartan & Hydrochlorothiazide; Drug: Flurbiprofen; Drug: Siponimod; Drug: Dicloxacillin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Warfarin oral clearance
Measured: 2 weeks
Formation clearance of CYP2C9 mediated warfarin metabolites
Measured: 2 weeks
Phenytoin Metabolic Ratio, oral clearance of Phenytoin, Formation clearance of p-HPPH.
Following single dose administration of Phenytoin 300 mg, at least two blood samples 12 and 24 hours post drug intake will be obtained and urine will be collected for at least 24 hours.
Measured: Up to 4 days (96 hours) post drug intake.
Losartan oral clearance and the formation clearance of E3174.
For those participant who receive losartan, blood sample will be collected periodically over 48 hours and urine will be collected for 48 hours. Losartan oral clearance and the formation clearance of E3174 will serve as primary outcomes.
Measured: Up to 48 hours post drug intake.
Flurbiprofen oral clearance.
Some participant will receive single dose of flurbiprofen 50 mg. Plasma samples will be obtained periodically over 24 hours and urine will be collected.
Measured: Up to 36 hours post drug intake.
Siponimod oral clearance.
Some participants will receive single dose of siponimod 0.25 mg and blood samples will be obtained periodically over the next 2 weeks. Pharmacodynamic response will be evaluated by repeated ECG records and measurement of CBC and potassium.
Measured: Up to 2 weeks following drug intake.
Change in S-warfarin and phenytoin pharmacokinetic parameters.
Some patients will receive phenytoin (300 mg) and at least one week later warfarin (20 mg) twice before and after intake of dicloxacillin 500 mg QID for 21 days.
Measured: Up to 6 weeks following the administration of the first warfarin single dose.
Correlation between CYP2C9 substrate pharmacokinetics and genetic polymorphism.
Using candidate gene approach, sequencing of relevant regions in chromosome 10 will be conducted. Potential genetic alterations (SNPs, deletions, insertions, p-VNTR) will be correlated with pharmacokinetic parameters of CYP2C9 substrates.
Measured: For up to 5 years following drug intake.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Sep 2005 (estimated)
- Study startSep 2003
- Primary completionDec 2030 (estimated)
- Study completionDec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The activity of CYP2C9 will be evaluated using several known substrates such as warfarin, phenytoin, losartan and flurbiprofen. To explore possible interethnic differences, healthy subjects of different ethnic backgrounds will be recruited.
- Masking
- None (open label)
- Enrolment
- 1,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Hadassah Medical Organization
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Yoseph Caraco, MD, Principal investigator, Hadassah Medical Organization
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00162474
- Sponsor's protocol ID
- yc195510-HMO-CTIL
- Status last verified
- Mar 2026
- First submitted
- 11 Sep 2005
- Last updated
- 21 Apr 2026
- Results posted
- No
Publications
Shaul C, Blotnick S, Muszkat M, Bialer M, Caraco Y. Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects. Mol Diagn Ther. 2017 Feb;21(1):75-83. doi: 10.1007/s40291-016-0247-7.
PubMed 27878474
Study at a glance
From the registry record, last updated by the sponsor on 21 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Correlation Between Phenotypic Activity of CYP2C9 and Genetic Polymorphism in CYP2C9 and Warfarin Metabolism.
- ClinicalTrials.gov ID
- NCT00162474
- Acronym / sponsor ID
- yc195510-HMO-CTIL
- Conditions
- Healthy
- Keywords
- Healthy Volunteers
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 1,000 participants (estimated)
- Lead sponsor
- Hadassah Medical OrganizationUniversity, hospital or other
- Study start
- Sep 2003 (actual)
- Primary completion
- Dec 2030 (estimated)
- Study completion
- Dec 2030 (estimated)
- First posted
- 13 Sep 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The anticoagulant effect of warfarin varies greatly among individuals. Some of this variability is attributed to differences in the activity of CYP2C9, the predominant enzyme involved in the metabolism of S-warfarin.
The present study is designed to define the differences in warfarin metabolism among healthy individuals carrying different CYP2C9 genotypes. In addition, the study will define the correlation between the phenytoin metabolic ratio, a marker of CYP2C9 activity in vivo, and warfarin metabolism.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The activity of CYP2C9 will be evaluated using several known substrates such as warfarin, phenytoin, losartan and flurbiprofen. To explore possible interethnic differences, healthy subjects of different ethnic backgrounds will be recruited.
| Arm | Type | Receives |
|---|---|---|
| CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. | Experimental | Drug: Warfarin, Drug: Phenytoin, Drug: Losartan & Hydrochlorothiazide, Drug: Flurbiprofen, Drug: Siponimod, Drug: DicloxacillinEach participant may be given at least one of the following CYP2C9 substrates: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
Who may qualify
- Ages
- 20 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (2 listed)
- Age range of 20-50 years old
- The absence of significant disease states
Key exclusion criteria (4 listed)
- Known hypersensitivity to warfarin or phenytoin
- Known hepersensitivity to penicillins or cephalosporins (Dicloxacillin part)
- The presence of significant disease states
- Regular use of drugs (including birth control pills)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| WarfarinEach participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
| PhenytoinEach participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
| Losartan & HydrochlorothiazideEach participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
| FlurbiprofenEach participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
| SiponimodEach participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
| DicloxacillinTo explore possible effect of dicloxacillin on CYP2C9 activity, some participants will be administered single dose of warfarin and phenytoin before and after intake of dicloxacillin. | Drug | CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod. |
Primary outcome
Warfarin oral clearance
Time frame: 2 weeks
Formation clearance of CYP2C9 mediated warfarin metabolites
Time frame: 2 weeks
Phenytoin Metabolic Ratio, oral clearance of Phenytoin, Formation clearance of p-HPPH.
Time frame: Up to 4 days (96 hours) post drug intake.
Following single dose administration of Phenytoin 300 mg, at least two blood samples 12 and 24 hours post drug intake will be obtained and urine will be collected for at least 24 hours.
Losartan oral clearance and the formation clearance of E3174.
Time frame: Up to 48 hours post drug intake.
For those participant who receive losartan, blood sample will be collected periodically over 48 hours and urine will be collected for 48 hours. Losartan oral clearance and the formation clearance of E3174 will serve as primary outcomes.
Flurbiprofen oral clearance.
Time frame: Up to 36 hours post drug intake.
Some participant will receive single dose of flurbiprofen 50 mg. Plasma samples will be obtained periodically over 24 hours and urine will be collected.
Siponimod oral clearance.
Time frame: Up to 2 weeks following drug intake.
Some participants will receive single dose of siponimod 0.25 mg and blood samples will be obtained periodically over the next 2 weeks. Pharmacodynamic response will be evaluated by repeated ECG records and measurement of CBC and potassium.
Change in S-warfarin and phenytoin pharmacokinetic parameters.
Time frame: Up to 6 weeks following the administration of the first warfarin single dose.
Some patients will receive phenytoin (300 mg) and at least one week later warfarin (20 mg) twice before and after intake of dicloxacillin 500 mg QID for 21 days.
Correlation between CYP2C9 substrate pharmacokinetics and genetic polymorphism.
Time frame: For up to 5 years following drug intake.
Using candidate gene approach, sequencing of relevant regions in chromosome 10 will be conducted. Potential genetic alterations (SNPs, deletions, insertions, p-VNTR) will be correlated with pharmacokinetic parameters of CYP2C9 substrates.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Apr 2026.
- Derived from this study: PubMed 27878474Shaul C, Blotnick S, Muszkat M, Bialer M, Caraco Y. Quantitative Assessment of CYP2C9 Genetic Polymorphisms Effect on the Oral Clearance of S-Warfarin in Healthy Subjects. Mol Diagn Ther. 2017 Feb;21(1):75-83. doi: 10.1007/s40291-016-0247-7.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Yoseph Caraco, MD principal investigator
Hadassah Medical Organization
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Warfarin, Phenytoin and Losartan & Hydrochlorothiazide in people with Healthy, run by Hadassah Medical Organization at 1 site in Israel.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 21 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Israel. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Yoseph Caraco, MD (00 972 2 6779373, caraco.yoseph@mail.huji.ac.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Warfarin oral clearance (time frame: 2 weeks). The study lists 8 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00162474, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Apr 2026.