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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Warfarin | Drug | Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
|
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Yoseph Caraco, MD | Contact | 00 972 2 6779373 | caraco.yoseph@mail.huji.ac.il |
| Name | Affiliation | Role |
|---|---|---|
| Yoseph Caraco, MD | Hadassah Medical Organization | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hadassah Medical Organization | Recruiting | Jerusalem | Israel |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27878474 | Derived | 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. |
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| ID | Term |
|---|---|
| D014859 | Warfarin |
| D010672 | Phenytoin |
| C505809 | hydrochlorothiazide, losartan drug combination |
| D005480 | Flurbiprofen |
| C578989 | siponimod |
| D004009 | Dicloxacillin |
| ID | Term |
|---|---|
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006573 |
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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.
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| Phenytoin | Drug | Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
|
| Losartan & Hydrochlorothiazide | Drug | Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
|
| Flurbiprofen | Drug | Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
|
| Siponimod | Drug | Each participant may be given at least one CYP2C9 substrate from the following list: Warfarin, Phenytoin, Losartan, Flurbiprofen and Siponimod. |
|
| Dicloxacillin | Drug | 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. |
|
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. |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006827 | Hydantoins |
| D048289 | Imidazolidines |
| D007093 | Imidazoles |
| D001393 | Azoles |
| D011422 | Propionates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D009930 | Organic Chemicals |
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D003023 | Cloxacillin |
| D010068 | Oxacillin |
| D010406 | Penicillins |
| D047090 | beta-Lactams |
| D007769 | Lactams |
| D000577 | Amides |
| D013457 | Sulfur Compounds |