CYP2B6 Polymorphisms in Methadone Disposition

This investigation determined the influence of CYP2B6 genetic variation, specifically
CYP2B6*6 polymorphism, on clinical methadone plasma concentrations, clearance, and
metabolism. The hypothesis was that CYP2B6*6 heterozygotes or homozygotes would have reduced
metabolism and clearance. A secondary objective was to evaluate other less common genotypic
variants, when encountered. Healthy volunteers in genotype cohorts CYP2B6*1/*1, CYP2B6*1/*6 ,
and CYP2B6*6/*6, and also CYP2B6*4 and CYP2B6*5 carriers, received single doses of IV and
oral methadone. Plasma and urine methadone and metabolite concentrations were determined by
tandem mass spectrometry. The primary outcome measure was methadone metabolism, measured as
plasma metabolite/patent area under the concentration-time curve ratio and metabolite
formation clearance.

Inclusion Criteria:

Each subject must meet all of the following criteria:

- 18-50 yr old

- CYP2B6*1/*1, CYP2B6*1/*6 or CYP2B6*6/*6 genotype

- Good general health with no remarkable medical conditions

- BMI < 33

- Provided informed consent

Exclusion Criteria:

Subjects will not be enrolled if any of the following criteria exist:

- Known history of liver or kidney disease

- Use of prescription or non prescription medications, herbals or foods known to be
metabolized by or affect CYP2B6

- Females who are pregnant or nursing

- Known history of drug or alcohol addiction (prior or present addiction or treatment
for addiction)

- Direct physical access to and routine handling of addicting drugs in the regular
course of duty (this is a routine exclusion from studies of drugs with addiction
potential)