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 Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
1,000
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Hadassah Medical Organization
Jerusalem, Israel
RECRUITINGWarfarin 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.
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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
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Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod.
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.
Time frame: 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.
Time frame: For up to 5 years following drug intake.