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

Condition(s) targeted: Substance-Related Disorders

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

Phase: Phase 1

Status: Recruiting

Sponsored by: University of Washington

Official(s) and/or principal investigator(s):
Rheem A Totah, PhD, Principal Investigator, Affiliation: University of Washington, Medicinal Chemistry Department

Overall contact:
Jean C Dinh, PharmD, Phone: 206.616.2775, Email: jeandinh@u.washington.edu

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

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

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

Primary outcome: 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.

Secondary outcome:

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).

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.

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.

Minimum age: 18 Years. Maximum age: 40 Years. Gender(s): Both.

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

Jean C Dinh, PharmD, Phone: 206.616.2775, Email: jeandinh@u.washington.edu

University of Washington General Clinical Research Center, Seattle, Washington 98105, United States; Recruiting
Rheem A Totah, PhD, Principal Investigator
Danny Shen, PhD, Principal Investigator
Gregory Terman, MD, Sub-Investigator
Kristin K Patton, MD, Sub-Investigator
Jean C Dinh, BS, Sub-Investigator

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Starting date: July 2007
Last updated: October 11, 2010