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

University of Washington

Status and phase: Unknown; Phase 1

Conditions: Substance-Related Disorders

Treatments: Drug: Bupropion (drug); Drug: midazolam(drug), digoxin (drug); Drug: Methadone (drug)

Study type: Interventional

Funder types: Other

Identifiers

NCT00504413

30931-A

06-3659-A 01

Details and patient eligibility

About

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

Full 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.

Enrollment: 20 estimated patients

Sex: All

Ages: 18 to 40 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)