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

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.

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