Determinants of Warfarin Metabolism

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.

Study Overview

• Status: Recruiting
• Conditions: Healthy
• Intervention / Treatment: Drug: Warfarin; Drug: Phenytoin; Drug: Losartan & Hydrochlorothiazide; Drug: Flurbiprofen; Drug: Siponimod; Drug: Dicloxacillin

• Study Type: Interventional
• Enrollment (Estimated): 1000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Yoseph Caraco, MD; Phone Number: 00 972 2 6779373; Email: caraco.yoseph@mail.huji.ac.il

Study Locations

• Israel
  • Jerusalem, Israel
    • Recruiting
    • Hadassah Medical Organization
    • Principal Investigator: Yoseph Caraco, MD
    • Contact: Hadas Lemberg, PhD; Phone Number: 00 972 2 6777572; Email: lhadas@hadassah.org.il
    • Contact: Arik Tzukert, DMD; Phone Number: 00 972 2 6776095; Email: arik@hadassah.org.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age range of 20-50 years old
• The absence of significant disease states

Exclusion Criteria:

• 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CYP2C9 substrate: Warfarin, Phenytoin, Losartan, Flurbiprofen, Siponimod.; Each participant may be given at least one of the following CYP2C9 substrates: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.

Drug: Warfarin; Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.; Drug: Phenytoin; Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.; Drug: Losartan & Hydrochlorothiazide; Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.; Drug: Flurbiprofen; Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.; Drug: Siponimod; Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.; Drug: Dicloxacillin; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Warfarin oral clearance		2 weeks
Formation clearance of CYP2C9 mediated warfarin metabolites		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.	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.	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.	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.	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.	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.	For up to 5 years following drug intake.

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization
• Investigators: Principal Investigator: Yoseph Caraco, MD, Hadassah Medical Organization

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2003
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: September 11, 2005
• First Submitted That Met QC Criteria: September 11, 2005
• First Posted (Estimated): September 13, 2005

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 16, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Healthy Volunteers
• Additional Relevant MeSH Terms: Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Azoles; Hydrocarbons; Hydrocarbons, Cyclic; Acids, Acyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Imidazoles; Amides; Benzene Derivatives; beta-Lactams; Lactams; Coumarins; Benzopyrans; Penicillins; Propionates; Biphenyl Compounds; 4-Hydroxycoumarins; Hydantoins; Imidazolidines; Oxacillin; Cloxacillin; Warfarin; Phenytoin; Flurbiprofen; Dicloxacillin; siponimod; hydrochlorothiazide, losartan drug combination
• Other Study ID Numbers: yc195510-HMO-CTIL