Pharmacogenetics of Warfarin Induction and Inhibition
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 60 |
| Updated: | 11/16/2018 |
| Start Date: | May 2009 |
| End Date: | June 2013 |
This research study will help determine how a person's genetic makeup affects their response
to drugs, the ability of the body to break down drugs, and their potential to experience an
interaction between drugs. The investigators are investigating the drug interactions with the
commonly used anticoagulant drug called warfarin. Warfarin is used for the treatment and
prevention of life-threatening abnormal blood clots such as deep vein thrombosis, heart
attacks, and strokes. The investigators chose warfarin for this study because it is a
commonly used drug and must be monitored closely to avoid side effects. The investigators are
interested in studying whether individuals with certain genetic profiles react differently to
warfarin when it is combined with other drugs. This research is being done to see if certain
genetic profiles require us to adjust warfarin doses differently than is needed for the
general population. Genetic profiles of subjects are determined from their participation in
the Pharmacogenetics Registry study (investigator Richard Brundage, University of Minnesota).
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the
warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive
interaction.
to drugs, the ability of the body to break down drugs, and their potential to experience an
interaction between drugs. The investigators are investigating the drug interactions with the
commonly used anticoagulant drug called warfarin. Warfarin is used for the treatment and
prevention of life-threatening abnormal blood clots such as deep vein thrombosis, heart
attacks, and strokes. The investigators chose warfarin for this study because it is a
commonly used drug and must be monitored closely to avoid side effects. The investigators are
interested in studying whether individuals with certain genetic profiles react differently to
warfarin when it is combined with other drugs. This research is being done to see if certain
genetic profiles require us to adjust warfarin doses differently than is needed for the
general population. Genetic profiles of subjects are determined from their participation in
the Pharmacogenetics Registry study (investigator Richard Brundage, University of Minnesota).
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the
warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive
interaction.
The research question is: How does CYP2C9 genotype modify warfarin drug interactions?
People differ in their genetic makeup. This includes differences in genes involved in drug
metabolism, transport, and effect in the body. People with certain genetic profiles produce
altered enzymes, transporters, and receptors that may respond in different ways to drugs.
Altered enzymes cause some drugs to be broken down at a different rate than normal. As a
result, drug concentrations build up in the blood, and increase the risk of side effects.
Furthermore, when two drugs are taken together, the possibility exists for the drugs to
interact, with one drug causing a change in the metabolism of the other or both of the drugs.
It is not known whether people with an altered genetic makeup also have an altered experience
with drug interactions. Altered drug transporters can affect the absorption and elimination
of drugs as compared to normal causing differences in how long the drug stays in the body.
Finally, altered drug receptors can respond differently to drugs and, thus, produce altered
desired or undesired effects.
In this study, the investigators will be investigating the drug interactions with the
commonly used anticoagulant drug warfarin in subjects with five different CYP2C9 genotypes.
The CYP2C9 genotype is particularly important because this drug metabolizing enzyme governs
the metabolic clearance of the more potent chemical entity (the S-enantiomer) of the drug.
Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots
such as deep vein thrombosis, myocardial infarction, and strokes. The investigators chose
warfarin for this study because it is a commonly used drug and must be monitored closely to
avoid side effects. The investigators are interested in studying whether individuals with
certain genetic alleles of the CYP2C9 genotype react differently to warfarin when it is
combined with an antifungal (fluconazole) that inhibits CYP2C9-mediated metabolism and an
antibiotic (rifampin) that induces CYP2C9-mediated metabolism. This research is being done to
see if certain genetic profiles require us to adjust warfarin doses differently than is
needed for the general population.
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the
warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive
interaction.
People differ in their genetic makeup. This includes differences in genes involved in drug
metabolism, transport, and effect in the body. People with certain genetic profiles produce
altered enzymes, transporters, and receptors that may respond in different ways to drugs.
Altered enzymes cause some drugs to be broken down at a different rate than normal. As a
result, drug concentrations build up in the blood, and increase the risk of side effects.
Furthermore, when two drugs are taken together, the possibility exists for the drugs to
interact, with one drug causing a change in the metabolism of the other or both of the drugs.
It is not known whether people with an altered genetic makeup also have an altered experience
with drug interactions. Altered drug transporters can affect the absorption and elimination
of drugs as compared to normal causing differences in how long the drug stays in the body.
Finally, altered drug receptors can respond differently to drugs and, thus, produce altered
desired or undesired effects.
In this study, the investigators will be investigating the drug interactions with the
commonly used anticoagulant drug warfarin in subjects with five different CYP2C9 genotypes.
The CYP2C9 genotype is particularly important because this drug metabolizing enzyme governs
the metabolic clearance of the more potent chemical entity (the S-enantiomer) of the drug.
Warfarin is used for the treatment and prevention of life-threatening abnormal blood clots
such as deep vein thrombosis, myocardial infarction, and strokes. The investigators chose
warfarin for this study because it is a commonly used drug and must be monitored closely to
avoid side effects. The investigators are interested in studying whether individuals with
certain genetic alleles of the CYP2C9 genotype react differently to warfarin when it is
combined with an antifungal (fluconazole) that inhibits CYP2C9-mediated metabolism and an
antibiotic (rifampin) that induces CYP2C9-mediated metabolism. This research is being done to
see if certain genetic profiles require us to adjust warfarin doses differently than is
needed for the general population.
The study hypothesis is: Functionally defective CYP2C9 alleles attenuate the
warfarin-fluconazole inhibitory interaction and exacerbate the warfarin-rifampin inductive
interaction.
Inclusion Criteria:
- Subjects will be 18-60 years old.
- Women of child bearing age must be willing to use measures to avoid conception during
the study period.
- Subjects must agree not to take any known substrates, inhibitors, inducers or
activators of either CYP2C9 or CYP3A4 from 1 week prior to the start of each study
through the last day of study.
Exclusion Criteria:
- Current cigarette smoker
- Abnormal renal, liver function tests, physical exam, or recent history of hepatic,
renal, gastrointestinal or neoplastic disease.
- Allergy to warfarin, fluconazole or rifampin and other chemically related drugs.
- Recent ingestion (< 1 week) of any medication known to be metabolized by or alter
CYP2C9 or CYP3A4 activity.
- A positive pregnancy test at the time of the pharmacokinetic study.
- Lab tests indicative of abnormal blood clotting capacity.
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