Pharmacogenetics of Warfarin Induction and Inhibition
Condition: Healthy
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Control - Warfarin only; Fluconazole - Warfarin; Rifampin - Warfarin
Intervention type(s): Drug; Drug; Drug
Intervention description(s): A single 10 mg warfarin dose taken at the start of the study period. No other medications taken during this study period.; A single 10 mg warfarin dose taken at the start of the study period. 400 mg fluconazole taken every morning starting a week before the start of the study period and continuing throughout the study period.; A single 10 mg warfarin dose taken at the start of the study period. 300 mg rifampin taken every morning starting a week before the start of the study period and continuing throughout the study period.
Other intervention name(s): Coumadin; Diflucan; Coumadin; Rifadin; Coumadin
Intervention MeSH terms: Rifampin; Fluconazole; Warfarin
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Drug Interactions; Warfarin; Genetics; CYP2C9; Healthy Volunteers