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

Substance-Related Disorders Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00504413
• Other study ID #: 30931-A
• Secondary ID: 06-3659-A 01
• Status: Recruiting
• Phase: Phase 1
• First received: July 18, 2007
• Last updated: October 11, 2010
• Start date: July 2007
• Est. completion date: January 2011

Study information

• Verified date: October 2010
• Source: University of Washington
• Contact: Jean C Dinh, PharmD
• Phone: 206.616.2775
• Email: jeandinh[@]u.washington.edu
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: January 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

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

Study Design

Endpoint Classification: Pharmacokinetics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Substance-Related Disorders

Intervention

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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	University of Washington General Clinical Research Center	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
University of Washington

Country where clinical trial is conducted

United States, 

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* Note: There are 63 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.		two years	No
Secondary	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).		two years	No
Secondary	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.		two years	Yes