Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone
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|ClinicalTrials.gov Identifier: NCT00504413|
Recruitment Status : Unknown
Verified October 2010 by University of Washington.
Recruitment status was: Recruiting
First Posted : July 20, 2007
Last Update Posted : October 13, 2010
|Condition or disease||Intervention/treatment||Phase|
|Substance-Related Disorders||Drug: midazolam(drug), digoxin (drug) Drug: Bupropion (drug) Drug: Methadone (drug)||Phase 1|
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:
- Pgp limits the gastrointestinal absorption
- 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Primary Purpose:||Basic Science|
|Official Title:||Role of CYP2B6, CYP3A4, and MDR1 in the Metabolic Clearance of Methadone in Human Subjects|
|Study Start Date :||July 2007|
|Estimated Primary Completion Date :||January 2011|
|Estimated Study Completion Date :||January 2011|
- 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.
- 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.Other Name: Wellbutrin
- 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.
- 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. [ Time Frame: two years ]
- 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). [ Time Frame: two years ]
- 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. [ Time Frame: two years ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00504413
|Contact: Jean C Dinh, PharmDemail@example.com|
|Contact: Rheem A Totah, PhDfirstname.lastname@example.org|
|United States, Washington|
|University of Washington General Clinical Research Center||Recruiting|
|Seattle, Washington, United States, 98105|
|Principal Investigator: Rheem A Totah, PhD|
|Principal Investigator: Danny Shen, PhD|
|Sub-Investigator: Gregory Terman, MD|
|Sub-Investigator: Kristin K Patton, MD|
|Sub-Investigator: Jean C Dinh, BS|
|Principal Investigator:||Rheem A Totah, PhD||University of Washington, Medicinal Chemistry Department|