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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2010 by University of Washington.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
University of Washington
ClinicalTrials.gov Identifier:
NCT00504413
First received: July 18, 2007
Last updated: October 11, 2010
Last verified: October 2010
  Purpose

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


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

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects

Resource links provided by NLM:


Further study details as provided by University of Washington:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: July 2007
Estimated Study Completion Date: January 2011
Estimated Primary Completion Date: January 2011 (Final data collection date for primary outcome measure)
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.
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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00504413

Contacts
Contact: Jean C Dinh, PharmD 206.616.2775 jeandinh@u.washington.edu
Contact: Rheem A Totah, PhD 206.543.9481 rtotah@u.washington.edu

Locations
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
Investigators
Principal Investigator: Rheem A Totah, PhD University of Washington, Medicinal Chemistry Department
  More Information

Publications:
Ward J, Mattrick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Harwood Academic Publishers, Amsterdam. 1998
Mercandante, S. Methadone in cancer pain. Eur J Pain 1:77, 1997.
Rosner B. Fundamentals of Biostatistics. Duxbury, 2006.

Responsible Party: Rheem Totah/Assistant Professor, Medicinal Chemistry, University of Washington
ClinicalTrials.gov Identifier: NCT00504413     History of Changes
Other Study ID Numbers: 30931-A, 06-3659-A 01
Study First Received: July 18, 2007
Last Updated: October 11, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by University of Washington:
Metabolic Networks and Pathways
Methadone
Polymorphism, genetic
Cytochrome P-450 Enzyme System

Additional relevant MeSH terms:
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Digoxin
Midazolam
Methadone
Bupropion
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Cardiotonic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Adjuvants, Anesthesia
Central Nervous System Agents
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Analgesics, Opioid

ClinicalTrials.gov processed this record on September 11, 2014