Advertisement

Topics

Effects of Genotype on CYP2C9 Drug Interactions

2014-08-27 03:16:13 | BioPortfolio

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 Timothy S. Tracy, 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.

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 alleles of the CYP2C9 genotype. 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 Design

Observational Model: Case-Crossover, Time Perspective: Prospective

Conditions

Healthy

Intervention

Pharmacogenetics

Location

Clinical and Translational Science Institute
Minneapolis
Minnesota
United States
55414

Status

Enrolling by invitation

Source

University of Minnesota - Clinical and Translational Science Institute

Results (where available)

View Results

Links

Published on BioPortfolio: 2014-08-27T03:16:13-0400

Clinical Trials [45 Associated Clinical Trials listed on BioPortfolio]

Influence of Intestinal Transporter Genetic Variants on the Bioavailability of Gabapentin

The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. Previously, we have recruited a cohort of healthy volun...

Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides

The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters. Previously, the investigators have recruited a cohort o...

Validation of Pharmacogenetics Plus Drug Combination Guided Initial Tacrolimus Dosage in Renal Transplant Recipients

The purpose of this study is to compare pharmacogenetics plus drug combination (Schisandra sphenanthera extract,SchE)guided and standard initial tacrolimus dosage.

Placebo Effect of Paracetamol in Healthy Volunteers

Paracetamol is one of the most commonly used drugs in the world, indicated for the symptomatic treatment of fever and pain of mild to moderate. More precisely, it is a drug used to relieve...

Use of Pharmacogenetics in the Treatment of Children With Autistic Spectrum Disorders

Children with autism are often treated with psychiatric drugs. These medications have been shown to improve their language and social function, and are important in improving their quality...

PubMed Articles [4442 Associated PubMed Articles listed on BioPortfolio]

Pharmacogenetics of Clopidogrel Therapy and Neurointerventional Procedures: We Need Precision Data for Precision Medicine.

Genetics has given a real boost to personalized and precision medicine, providing data used either for precise diagnostics, prediction of the course of illness, or for selecting therapy and tailoring ...

Whole-genome methylation profiling of peripheral blood mononuclear cell for acute exacerbations of chronic obstructive pulmonary disease treated with corticosteroid.

Although association studies in the general population may be relevant for determining susceptibility to chronic obstructive pulmonary disease (COPD), they may be less applicable for pharmacogenetics ...

Pharmacogenetics of the anti-HCV drug sofosbuvir: a preliminary study.

Sofosbuvir is a potent nucleotide HCV NS5B polymerase inhibitor that is also a P-glycoprotein (encoded by the ABCB1 gene) and breast cancer resistance protein (encoded by the ABCG2 gene) substrate. Co...

Pharmacogenetic testing in the Veterans Health Administration (VHA): policy recommendations from the VHA Clinical Pharmacogenetics Subcommittee.

The Veterans Health Administration (VHA) Clinical Pharmacogenetics Subcommittee is charged with making recommendations about whether specific pharmacogenetic tests should be used in healthcare at VHA ...

Pharmacogenetics and the Promise of Personalized Medicine.

Medical and Biotech [MESH] Definitions

Healthy People Programs are a set of health objectives to be used by governments, communities, professional organizations, and others to help develop programs to improve health. It builds on initiatives pursued over the past two decades beginning with the 1979 Surgeon General's Report, Healthy People, Healthy People 2000: National Health Promotion and Disease Prevention Objectives, and Healthy People 2010. These established national health objectives and served as the basis for the development of state and community plans. These are administered by the Office of Disease Prevention and Health Promotion (ODPHP). Similar programs are conducted by other national governments.

Governmental guidelines and objectives pertaining to public food supply and nutrition including recommendations for healthy diet and changes in food habits to ensure healthy diet.

The detection of genetic variability (e.g., PHARMACOGENOMIC VARIANTS) relevant to PHARMACOGENETICS and PRECISION MEDICINE. The purpose of such genetic testing is to help determine the most effective treatment options and their optimum dosages with least potential risks for DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS.

Surgical reinnervation of a denervated peripheral target using a healthy donor nerve and/or its proximal stump. The direct connection is usually made to a healthy postlesional distal portion of a non-functioning nerve or implanted directly into denervated muscle or insensitive skin. Nerve sprouts will grow from the transferred nerve into the denervated elements and establish contact between them and the neurons that formerly controlled another area.

Dietary patterns which have been found to be important in reducing disease risk.

More From BioPortfolio on "Effects of Genotype on CYP2C9 Drug Interactions"

Advertisement
Quick Search
Advertisement
Advertisement

 

Relevant Topics

Drug Discovery
Clinical Approvals Clinical Trials Drug Approvals Drug Delivery Drug Discovery Generics Drugs Prescription Drugs In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are dis...

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...


Searches Linking to this Trial