Effects of Genotype on CYP2C9 Drug Interactions

July 15, 2019 updated by: University of Minnesota

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.

Study Overview

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.

Study Type

Observational

Enrollment (Actual)

23

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Minnesota
      • Minneapolis, Minnesota, United States, 55414
        • Clinical and Translational Science Institute

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 60 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Subjects are selected from a pharmacogenetics registry in which their drug metabolism genotype has been determined.

Description

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 CYP2C9.

Exclusion Criteria:

  • Current cigarette smoker.
  • Abnormal renal or liver function tests, physical exam, or recent history of hepatic, renal, gastrointestinal or neoplastic disease.
  • Allergy to tolbutamide, flurbiprofen, ketoprofen, fluconazole or phenytoin and other chemically related drugs.
  • Recent ingestion (< 1 week) of any medication known to be metabolized by or alter activity of CYP2C9.
  • A positive pregnancy test during the time of the pharmacokinetic study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
CYP2C9*1/*1 Genotype
This genotype is considered the wild type genotype. Individuals with the CYP2C9*1/*1 genotype have two *1 alleles and participated in the following interventions: Flurbiprofen Control - Flurbiprofen Only, Flurbiprofen Inhibition - Flurbiprofen & Fluconazole, Ketoprofen Control - Ketoprofen Only, Ketoprofen Inhibition - Ketoprofen & Fluconazole, Tolbutamide Control - Tolbutamide Only, and Tolbutamide Inhibition - Tolbutamide & Fluconazole.
A single 50 mg flurbiprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Ansaid
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.
Other Names:
  • Diflucan
  • Ansaid
A single 75 mg ketoprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orudis
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.
Other Names:
  • Diflucan
  • Orudis
A single 500 mg tolbutamide dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orinase
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 Names:
  • Diflucan
  • Orinase
CYP2C9*1/*3 Genotype
Individuals with the CYP2C9*1/*3 genotype have one *1 allele and one *3 allele and participated in the following interventions: Flurbiprofen Control - Flurbiprofen Only, Flurbiprofen Inhibition - Flurbiprofen & Fluconazole, Ketoprofen Control - Ketoprofen Only, Ketoprofen Inhibition - Ketoprofen & Fluconazole, Tolbutamide Control - Tolbutamide Only, and Tolbutamide Inhibition - Tolbutamide & Fluconazole.
A single 50 mg flurbiprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Ansaid
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.
Other Names:
  • Diflucan
  • Ansaid
A single 75 mg ketoprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orudis
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.
Other Names:
  • Diflucan
  • Orudis
A single 500 mg tolbutamide dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orinase
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 Names:
  • Diflucan
  • Orinase
CYP2C9*3/*3 Genotype
Individuals with the CYP2C9*3/*3 genotype have two *3 alleles and participated in the following interventions: Flurbiprofen Control - Flurbiprofen Only, Flurbiprofen Inhibition - Flurbiprofen & Fluconazole, Ketoprofen Control - Ketoprofen Only, Ketoprofen Inhibition - Ketoprofen & Fluconazole, Tolbutamide Control - Tolbutamide Only, and Tolbutamide Inhibition - Tolbutamide & Fluconazole.
A single 50 mg flurbiprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Ansaid
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.
Other Names:
  • Diflucan
  • Ansaid
A single 75 mg ketoprofen dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orudis
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.
Other Names:
  • Diflucan
  • Orudis
A single 500 mg tolbutamide dose taken at the start of the study period. No other drugs administered during this study period.
Other Names:
  • Orinase
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 Names:
  • Diflucan
  • Orinase

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Flurbiprofen Clearance
Time Frame: 48 hours post Flurbiprofen dose
Measure of blood concentrations of Flurbiprofen 48 hours post Flurbiprofen dose
48 hours post Flurbiprofen dose
Ketoprofen Clearance
Time Frame: 48 hours post Ketoprofen dose
Measure of blood concentrations of Ketoprofen 48 hours post Ketoprofen dose
48 hours post Ketoprofen dose
Tolbutamide Clearance
Time Frame: 48 hours post Tolbutamide dose
Measure of blood concentrations of Tolbutamide 48 hours post Tolbutamide dose
48 hours post Tolbutamide dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Richard Brundage, PhD, University of Minnesota

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 1, 2009

Primary Completion (Actual)

June 1, 2014

Study Completion (Actual)

June 1, 2014

Study Registration Dates

First Submitted

January 29, 2010

First Submitted That Met QC Criteria

February 1, 2010

First Posted (Estimate)

February 2, 2010

Study Record Updates

Last Update Posted (Actual)

July 18, 2019

Last Update Submitted That Met QC Criteria

July 15, 2019

Last Verified

July 1, 2019

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Healthy

Clinical Trials on Flurbiprofen Control - Flurbiprofen Only

3
Subscribe