Effects of Genotype on CYP2C9 Drug Interactions
Condition: Healthy
Study type: Observational

Summary: 
      This research study will help determine how a person's genetic makeup affects their responses
      to drugs, the ability of the body to break down drugs, and their potential to experience an
      interaction between drugs. We are investigating the drug interactions between an antifungal
      drug called fluconazole and the commonly used drugs tolbutamide, flurbiprofen, and
      ketoprofen. Tolbutamide is used for management of Type 2 diabetes. Both flurbiprofen and
      ketoprofen are non-steroidal anti-inflammatory drugs (NSAIDs) often used for arthritis or
      pain. We are interested in studying whether individuals with certain genetic profiles have
      different drug interactions than normal. This research is being done to see if certain
      genetic profiles require us to adjust medication doses differently than is needed for the
      general population. Genetic profiles of subjects are determined from their previous
      participation in the Pharmacogenetics Registry (Investigator Richard Brundage, University of
      Minnesota).

      The study hypothesis is: Fraction metabolized by CYP2C9 enzyme determines the extent of drug
      interactions in CYP2C9*1/*1 individuals but this factor (fraction metabolized) becomes less
      influential and drug interactions are attenuated in a gene-dose dependent manner in
      individuals with one or more defective alleles.
    

Detailed description: 
      The study hypothesis is: Fraction metabolized by CYP2C9 enzyme determines the extent of drug
      interactions in CYP2C9*1/*1 individuals but this factor (fraction metabolized) becomes less
      influential and drug interactions are attenuated in a gene-dose dependent manner in
      individuals with one or more defective alleles.

      Objective: Examine the extent of fluconazole inhibition of drugs with varying degrees of
      fraction metabolized by CYP2C9 in individuals with the CYP2C9*1/*1, CYP2C9*1/*3 and
      CYP2C9*3/*3 genotypes.

      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, we will be investigating the drug interactions between an antifungal drug
      called fluconazole and the commonly used drugs tolbutamide, flurbiprofen, and ketoprofen in
      subjects with three different genotypes of the CYP2C9 enzyme. Tolbutamide is used for
      management of Type 2 diabetes. Both flurbiprofen and ketoprofen are non-steroidal
      anti-inflammatory drugs (NSAIDs) often used for arthritis or pain. We are interested in
      studying whether individuals with certain genetic profiles have different drug interactions
      than normal. This research is being done to see if certain genetic profiles require us to
      adjust medication doses differently than is needed for the general population.

      The cytochrome P450 (CYP) superfamily of enzymes plays an important role in the oxidative
      conversion of numerous xenobiotics into their more hydrophilic metabolites. CYP2C9, is an
      important member of the CYP superfamily, accounting for 10-20% of the CYP protein content in
      human liver and catalyzes approximately 20% of the CYP mediated drug oxidation reactions,
      including tolbutamide and the non-steroidal anti-inflammatory drugs (NSAIDs) such as
      ketoprofen and flurbiprofen. It is now well established that genetic factors play an
      important role in the control of CYP2C9 expression and activity. In particular, the *3 allele
      is expressed at an allele frequency of 15%. Homozygotic *3 individuals exhibit significantly
      reduced oral clearance for several CYP2C9 substrates. In most of these cases, the reduction
      in clearance approaches 80% and even in heterozygotic individuals, this reduction in
      clearance is 40-50% due to the co-dominant expression of CYP2C9. This reduction in clearance
      has been associated with an increased frequency of adverse events following warfarin or
      phenytoin administration, two clinically important drugs that exhibit a narrow therapeutic
      index. The therapeutic index is a comparison of the amount of a therapeutic agent that causes
      the therapeutic effect to the amount that causes toxic effects.
    

Intervention name(s): Flurbiprofen Control - Flurbiprofen Only; Flurbiprofen Inhibition - Flurbiprofen & Fluconazole; Ketoprofen Control - Ketoprofen Only; Ketoprofen Inhibition - Ketoprofen & Fluconazole; Tolbutamide Control - Tolbutamide Only; Tolbutamide Inhibition - Tolbutamide & Fluconazole
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): A single 50 mg flurbiprofen dose taken at the start of the study period. No other drugs administered during this study period.; A single 50 mg flurbiprofen 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 75 mg ketoprofen dose taken at the start of the study period. No other drugs administered during this study period.; A single 75 mg ketoprofen 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 500 mg tolbutamide dose taken at the start of the study period. No other drugs administered during this study period.; A single 500 mg tolbutamide 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.
Other intervention name(s): Ansaid; Ansaid; Diflucan; Orudis; Orudis; Diflucan; Orinase; Orinase; Diflucan
Intervention MeSH terms: Tolbutamide; Fluconazole; Ketoprofen; Flurbiprofen
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Subjects are selected from a pharmacogenetics registry in which their drug metabolism
        genotype has been determined.
      
Biospecimen description: 
      Plasma and urine samples are to be retained.
    
Keywords: Drug Interactions; Genetics; CYP2C9; Healthy Volunteers