Molecule of the Month
July 1999

Zyban (Bupropion)

Jamie Harris and Dr. Bernard Blessington
Pharmaceutical Chemistry, Bradford University, UK

This month's MOTM is the result of a Chemistry-based web browser race held in the Pharmaceutical Chemistry Department of Bradford University. In this, students on the course were asked the question: "What is Zyban and its uses?", and they had to race to find the relevant information using web-based resources. The first student to obtain sufficient information, including 3D chemical structures, medical uses, side-effects, etc, won the prize. This year it was won by Jamie Harris, a 1st Year Pharmacy undegraduate at Bradford, who obtained the following information in one day.

Zyban - a new treatment for nicotine addiction

Zyban is a drug marketed by Glaxo-Wellcome and has been used, very successfully, to treat nicotine addiction directly. In this case it is different to the way other anti-smoking agents work, such as nicotine gum and patches, since these simply supply an alternative source of nicotine other than cigarettes. Zyban works at the neurological level, reducing the craving for nicotine in any form. At the moment it is licensed in the US, but not yet in the UK. It is potentially extremely important, as this discovery could open the door to finding similar molecules for treating much more serious addiction problems, such as cocaine and heroin, etc.

Zyban (bupropion hypochloride)        
Zyban (bupropion hypochloride)

Also available (left-click to download): 		Zyban - Click for 3D structure

The active ingredient in Zyban is bupropion, a relatively weak inhibitor of the neuronal uptake of dopamine, serotonin and norepinephrine. Chemically, bupropion is related to phenylethylamines and has a relative molecular weight of 276.2. Although, bupropion was initially marketed as an anti-depressant (Wellbutrin), it is chemically unrelated to tricyclic, tetracyclic, selective serotonin reuptake inhibitors or other known anti-depressants.

The pharmacokinetics of bupropion is best described by a two-compartment model with a distribution phase (how long it takes for the drug to be absorbed into the body and begin working) having a mean half-life of 3-4 hours, and an elimination phase (how long it takes for it to be metabolised and broken down to inert waste products) which has a half-life of 21 hours. Bupropion is extensively metabolized into three active metabolites. At least one of these metabolites is formed by an enzyme called cytochrome P-450 2B6 enzyme. The terminal half-life of the three metabolites ranges from 21 to 37 hours. This means that it may interact with other drugs which also effect this enzyme, such as orphenadrine and cyclophosphamide. The main known side-effects of zyban are dry mouth and dizziness, although there are a few others.

Treatment method

The recommended and maximum dose of Zyban is 300 mg/day given as 150 mg tablets, twice daily. Treatment is usually initiated while the patient is still smoking and the target date for smoking cessation is normally within the first two weeks of Zyban treatment. Zyban therapy then continues for 7 to 12 weeks, depending on the effect of the therapy. If the patient has not reduced smoking by the seventh week of Zyban therapy, it is unlikely that he/she will quit during that attempt and Zyban therapy is normally discontinued.

More information from a Chemical/Pharmacological Perspective

Brand Name Zyban
Generic Name Bupropion Hydrochloride - Sustained Release Tablets
Company Glaxo-Wellcome
Indication(s) An aid to smoking cessation treatment.
Contraindications Patients treated with Wellbutrin or any other medications that contain bupropion, in patients with a current or prior diagnosis of bulimia or anorexia nervosa, in patients taking mono-amine oxidase inhibitors (MAOIs) and in patients who have shown a hypersensitivity to bupropion. Patients who have taken MAO inhibitors must wait at least 14 days between the discontinuation of MAO inhibitor therapy and the commencement of Zyban therapy.
Mechanism of Action Inhibitor of the neuronal uptake of norepinephrine, serotonin and dopamine.
Dosage Form(s) 150 mg tablets
Administration The recommended and maximum dose of Zyban is 300 mg/day given as 150 mg, twice daily. Dosing should begin at 150 mg/day for the first three days followed by an increase to the usual dose of 300 mg/day. Treatment should be initiated while the patient is still smoking and a target date for smoking cessation should be within the first two weeks of Zyban treatment. Zyban therapy should continue for 7 to 12 weeks, depending on the effect of the therapy. If the patient has not reduced smoking by the seventh week of Zyban therapy, it is unlikely that he/she will quit during that attempt and Zyban therapy should be discontinued.

Common Side Effects

Adverse events were compiled from two clinical studies, a dose-response trial and a comparator trial. Adverse events noted in the dose-response trial occurring at a frequency of greater than 2 % and greater in the Zyban group than in the Placebo group are listed in the following table:
Adverse Event Incidence Rate (%)
Zyban
100 - 300 mg/day
(n=461)		 Placebo
(n=150)
Dry mouth
Insomnia
Dizziness
Arthralgia
Pruritis
Rash		 11
31
8
4
3
3		 5
21
7
3
<1
<1

Adverse events noted in the comparator trial occurring at a frequency of greater than 2 % and greater in the Zyban group than in the Placebo group are listed in the following table:
Adverse
Event		 Adverse Event Incidence in Comparative Trials (%)
Zyban
300 mg/day
(n=243)		 Nicotine Transdermal System (NTS)
21 mg/day
(n=243)		 Zyban and NTS
(n=244)		 Placebo
(n=159)
Abdominal Pain
Nausea
Dry mouth
Constipation
Diarrhea
Anorexia
Myalgia
Arthralgia
Insomnia
Dream abnormality
Anxiety
Disturbed concentration
Dizziness
Nervousness
Rhinitis
Increased cough
Pharygitis
Application site reaction
Rash
Pruritis
Taste perversion		 3
9
10
8
4
3
4
5
40
5
8
9
10
4
12
3
3
11
4
3
3		 4
7
4
4
4
1
3
3
28
18
6
3
2
<1
11
5
2
17
3
1
1		 1
11
9
9
3
5
5
3
45
13
9
9
8
2
9
<1
3
15
3
5
3		 1
4
4
3
1
1
3
2
18
3
6
4
6
2
8
1
0
7
2
1
2

The second series of clinical trials examined the adverse events associated with Zofran treatment for the prevention of post-operative nausea and vomiting. These were placebo controlled trials:

Drug Interactions

In vitro studies indicate that bupropion is metabolized by the cytochrome P-450 2B6 enzyme. Therefore, there is potential for a drug interaction between Zyban and drugs that effect CYP2B6 such as orphenadrine and cyclophosphamide. Certain drugs such as carbamazepine, phenobarbitol, and phenytoin may induce the metabolism of bupropion while others such as cimetidine may inhibit its metabolism. No formal studies have been conducted in humans to assess the effects of drug interactions.

Bupropion is the same active ingredient found in the anti-depressant Wellbutrin. Therefore, patient's being treated for depression with Wellbutrin should not take Zyban as it would increase the plasma levels of bupropion.

Two clinical trials were carried out to determine the effectiveness of Zyban as an aid in smoking cessation. The first trial was a dose-response trial during which the endpoint was abstinence from week 4 of the study.
Abstinence From Week 4 through Specified Week Quit Rates by Treatment Groups (%)
Placebo
(n=151)		 Zyban
100 mg/day
(n=153)		 Zyban
200 mg/day
(n=153)		 Zyban
300 mg/day
(n=156)
Week 7 17 22 27 36
Week 12 14 20 20 25
Week 26 11 16 18 19

The second trial was a comparator trial that also measured abstinence from week 4 of the study.
Abstinence From Week 4 through Specified Week Quit Rates by Treatment Groups (%)
Placebo
(n=160)		 NTS
(n=244)		 Zyban
300 mg/day
(n=153)		 Zyban
300 mg/day and NTS
(n=245)
Week 7 23 36 49 58
Week 10 20 32 46 51

These pages are for information purposes only and do not constitute a recommendation or endorsement of the product. Consult your physician concerning the availability and usage of these drugs for your particular situation.

counter Back to Molecule of the Month page         [DOI:10.6084/m9.figshare.5462434].