Pharmacogenetics of Bupropion Metabolism

Bupropion is widely used in the treatment of depression and for smoking cessation. It's most abundant metabolite, hydroxybupropion, may be responsible for most of the therapeutic effect of bupropion under conditions of long term dosing. Because the primary enzyme involved in metabolism of bupropion to hydroxybupropion is the liver enzyme CYP2B6, we propose to study the effect of different CYP2B6 genotypes on the metabolism of bupropion. These data will guide the use of genotypes as a surrogate for measuring drug blood levels in studying genetic determinants of outcomes for bupropion treatment.

A minimum of Forty-four subjects with 4 different CYP2B6 genotypes will participate in a 7-day study in which they take bupropion as outpatients for 6 days (to achieve steady state drug levels) and then come to the San Francisco General Hospital (SFGH) Clinical Research Center for a 1-day admission during which multiple blood and urine samples will be collected for pharmacokinetic analysis.

Inclusion criteria

• Age: 18 - 65 years
• Gender: Either
• Ethnic/Racial Group: Any
• Smoking Status: Both smokers and non-smokers are eligible
• CYP2B6 genotype: CYP2B6 *1/*1 (11 subjects); *4, *5 and *6 alleles (11 each) [44 subjects total] Up to 15 additional subjects may be studied with genotypes that do not fall into one of the primary groups.

Exclusion criteria

• Medical: Exclude most any chronic illness requiring regular medication.
• Cardiac: History of angina or other serious heart disease; ECG abnormalities on screening.
• Hypertension: screening visit BP of 150/95 or more after 5 min rest
• Respiratory: Asthma - acceptable if in remission, otherwise exclude.
• Systemic: "Morbidly Obese" Exclude if BMI > 35
• Diabetes: By history
• Chronic Active Hepatitis: By history; elevated Liver Function Tests
• Cancers: By history
• Pregnancy/breastfeeding: By history; positive urine pregnancy test
• Seizures: individuals with a history of seizures will be excluded (risk factor for bupropion-induced seizures)
• Eating Disorders: individuals with a history of eating disorders will be excluded (risk factor for bupropion-induced seizures)
• Head Trauma: individuals with a history of head trauma will be excluded (risk factor for bupropion-induced seizures)
• Other tobacco users (pipe, cigar, chewing tobacco, snuff users
• Medications/Supplements: General Exclusion = "any regular oral and/or prescription drug use"; current use of oral contraceptives or other female hormones.
• Drug/alcohol use: no alcohol abuse by history, no regular recreational drug use, any intravenous drug abuse, recent history of Treatment program