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

NCT ID: NCT00504413

Last Updated: 2010-10-13

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE1

Total Enrollment

20 participants

Study Classification

INTERVENTIONAL

Study Start Date

2007-07-31

Study Completion Date

2011-01-31

Brief Summary

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

Detailed Description

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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.

Conditions

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Substance-Related Disorders

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

NONE

Interventions

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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.

Intervention Type 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.

Intervention Type 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.

Intervention Type DRUG

Other Intervention Names

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Wellbutrin

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

40 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University of Washington

OTHER

Sponsor Role lead

Responsible Party

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University of Washington

Principal Investigators

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Rheem A Totah, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Washington, Medicinal Chemistry Department

Locations

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University of Washington General Clinical Research Center

Seattle, Washington, United States

Site Status RECRUITING

Countries

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United States

Central Contacts

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Jean C Dinh, PharmD

Role: CONTACT

[email protected]
206.616.2775

Rheem A Totah, PhD

Role: CONTACT

[email protected]
206.543.9481

References

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Other Identifiers

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06-3659-A 01

Identifier Type: -

Identifier Source: secondary_id

30931-A

Identifier Type: -

Identifier Source: org_study_id