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Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00504413
Recruitment Status : Unknown
Verified October 2010 by University of Washington.
Recruitment status was:  Recruiting
First Posted : July 20, 2007
Last Update Posted : October 13, 2010
Information provided by:
University of Washington

Brief Summary:
The purpose of this study is to determine to what extent CYP2B6, CYP3A4, and MDR1 polymorphisms affect the metabolism of methadone.

Condition or disease Intervention/treatment Phase
Substance-Related Disorders Drug: midazolam(drug), digoxin (drug) Drug: Bupropion (drug) Drug: Methadone (drug) Phase 1

Detailed Description:

Methadone maintenance treatment (MMT) has been used to rehabilitate the opiate addict resulting in a higher quality of life for the patient as well as improving social and psychological functioning while reducing the overall cost to society. The maintenance dose of methadone is highly variable between patients, and drug-drug interactions have been observed between methadone and various medications used to treat a variety of diseases. Identification and understanding of the enzymes responsible for the metabolism of methadone could potentially lead to improved strategy in individualizing methadone dosing and reduce the risk of adverse drug interactions.

Several cytochrome P450 enzymes (CYPs) have been identified and hypothesized to be involved in methadone metabolism in vitro, particularly CYP2B6 and CYP3A4. However, the quantitative contribution of CYP2B6 and CYP3A4 in the elimination clearance of methadone in vivo remains undefined. In addition, methadone is a substrate of the efflux transporter, P-glycoprotein (Pgp) at the intestinal mucosa. We are proposing a pilot study in healthy human subjects to investigate the following hypotheses:

  1. Pgp limits the gastrointestinal absorption
  2. Inter-subject variations in CYP2B6 and CYP3A4 activities explain the variation in methadone clearance in vivo

This will be accomplished by correlating the pharmacokinetics of methadone and the phenotype probes for Pgp (digoxin), CYP2B6 (bupropion) and CYP3A4 (midazolam). We plan to use these data to design a human subject study to assess the utility of MDR1 and CYP genotyping in predicting the methadone maintenance dose in a cohort of MMT patients.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects
Study Start Date : July 2007
Estimated Primary Completion Date : January 2011
Estimated Study Completion Date : January 2011

Intervention Details:
  • Drug: midazolam(drug), digoxin (drug)
    Midazolam (2mg po) and digoxin (0.5mg po) will be administered one time, an hour apart. Blood concentration will be collected at various points in an 8 hour period.
  • Drug: Bupropion (drug)
    Bupropion (150mg po) will be administered one time on a separate visit. Blood concentrations will be collected at various points in a 72 hour period.
    Other Name: Wellbutrin
  • Drug: Methadone (drug)
    Methadone (10mg po) will be administered at a separate visit 2 weeks after the bupropion visit. The dose is given once. Blood concentrations will be measured at various points in a 72 hour period. Pupil constriction will be measured and urine will be collected during this period as well.

Primary Outcome Measures :
  1. Explore if there is a correlation between the areas of the concentration curves of probe substrates for CYP3A4 and/or CYP2B6 and Pgp and the area of the concentration curve of methadone. [ Time Frame: two years ]

Secondary Outcome Measures :
  1. LC-MS assays will be developed to analyze the plasma content of the probe substrates, methadone and their metabolites. Specifically, midazolam, 1-OH midazolam, bupropion, t-butyl-hydroxy bupropion, digoxin, methadone, and EDDP (a methadone metabolite). [ Time Frame: two years ]
  2. Isolate and bank the DNA of the subjects for future genotyping of variant alleles that will be identified in this study to be important in methadone pharmacokinetics. [ Time Frame: two years ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  • Healthy
  • Within 25% of ideal body weight

Exclusion Criteria:

  • Pregnant
  • A prisoner
  • Enemy, non-combatant
  • Smoker
  • Have a history of liver disease
  • Have a history of heart disease
  • Have a history of drug abuse
  • Currently on prescription medication

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00504413

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Contact: Jean C Dinh, PharmD 206.616.2775
Contact: Rheem A Totah, PhD 206.543.9481

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United States, Washington
University of Washington General Clinical Research Center Recruiting
Seattle, Washington, United States, 98105
Principal Investigator: Rheem A Totah, PhD         
Principal Investigator: Danny Shen, PhD         
Sub-Investigator: Gregory Terman, MD         
Sub-Investigator: Kristin K Patton, MD         
Sub-Investigator: Jean C Dinh, BS         
Sponsors and Collaborators
University of Washington
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Principal Investigator: Rheem A Totah, PhD University of Washington, Medicinal Chemistry Department
Ward J, Mattrick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, Amsterdam. 1998
Rosner B. Fundamentals of Biostatistics. Duxbury, 2006.
Allen DM. The prediction sum of squares as a criterion for selecting predictor variables. In University of Ky Dept of Statistics Tech Report 23, 1971

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Responsible Party: Rheem Totah/Assistant Professor, Medicinal Chemistry, University of Washington Identifier: NCT00504413    
Other Study ID Numbers: 30931-A
06-3659-A 01
First Posted: July 20, 2007    Key Record Dates
Last Update Posted: October 13, 2010
Last Verified: October 2010
Keywords provided by University of Washington:
Metabolic Networks and Pathways
Polymorphism, genetic
Cytochrome P-450 Enzyme System
Additional relevant MeSH terms:
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Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents, Second-Generation
Antidepressive Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Dopamine Agents
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors