Bupropion Usage And Synthesis

Uses

enteric coating

Definition

ChEBI: Bupropion is an aromatic ketone that is propiophenone carrying a tert-butylamino group at position 2 and a chloro substituent at position 3 on the phenyl ring. It has a role as an antidepressant, an environmental contaminant and a xenobiotic. It is a secondary amino compound, a member of monochlorobenzenes and an aromatic ketone.

Mechanism of action

Although the mechanism of antidepressant action for bupropion is unclear, in vitro binding studies show bupropion to be a selective inhibitor of dopamine reuptake at the dopamine presynaptic neuronal membrane and minimal inhibition of NE and 5-HT reuptake. Bupropion does not exhibit clinically significant anticholinergic, antihistaminic, α1-adrenergic blocking activity, or MAO inhibition. The mechanism of its antidepressant action is more complex because of bupropion's metabolism to its three principal metabolites, which likely contribute to the mechanism of action for bupropion because their plasma concentrations are as high or higher than those of bupropion, with a longer duration of action.
Bupropion reduces the discomfort and craving associated with smoking cessation, which suggests that the principal mode of action by bupropion as an aid in smoking cessation is on the withdrawal symptoms following smoking cessation. Its precise mechanism of action, however, remains unclear. The efficacy of bupropion in smoking cessation does not appear to depend on the presence of underlying depression. Bupropion increases extracellular dopamine concentrations in the CNS, most likely as a result of its inhibition of dopamine and noradrenaline reuptake transporters. It also has been shown to be an antagonist at the nicotinic receptor at clinically relevant concentrations of bupropion. As nicotine concentrations in the CNS drop with smoking cessation, the firing rates of noradrenergic neurons increase, which may be the basis for the withdrawal symptoms. Thus, during withdrawal, bupropion and its active metabolite, hydroxybupropion, reduce the firing rates of these noradrenergic neurons in a dose-dependent manner, attenuating the symptoms of smoking cessation. Furthermore, its ability to antagonize nicotinic receptors also may prevent relapse by attenuating the reinforcing properties of nicotine but probably cannot acutely reduce smoking. Bupropion is extensively metabolized in humans with its major hydroxylated metabolites reaching plasma levels higher than those of bupropion itself. These hydroxylated metabolites share many of the pharmacological properties of bupropion, so they may play a greater role in attenuating the withdrawal and relapse by which bupropion exerts its activity in smoking cessation.

Pharmacokinetics

Bupropion is absorbed from the GI tract, with a low oral bioavailability as a result of first-pass metabolism.Food does not appear to substantially affect its peak plasma concentration or AUC. Following oral administration, peak plasma concentrations usually are achieved within 2 hours for bupropion and 3 hours for sustained-released bupropion products, followed by a biphasic decline for bupropion. Plasma concentrations are dose-proportional (linear pharmacokinetics) following single doses of 100 to 250 mg/day. The fraction of a dose excreted unmetabolized was less than 1%.Bupropion hydroxylation of the tert-butyl group to hydroxypropion is mediated almost exclusively by CYP2B6 and, to a lesser extent, by CYP2E1. Other metabolites include reduction of the aminoketone to aminoalcohol isomers, threo-hydrobupropion and erythro-hydrobupropion. Further oxidation of the bupropion side chain results in the formation of m-chlorobenzoic acid, which is eliminated in the urine as its glycine conjugate. Hydroxybupropion is approximately 50% as potent as bupropion, whereas threohydrobupropion and erythro-hydrobupropion have 20% of the potency of bupropion. Peak plasma concentrations for hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state, with an elimination half-life of approximately 20 hours. The times to peak concentrations for the erythro-hydrobupropion and threo-hydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. The plasma levels of the erythro-hydrobupropion correlate with several side effects, such as insomnia and dry mouth. Their elimination half-lives, however, are longer (~33 and 37 hours, respectively), and steady-state AUCs are 1.5- and 7.0 times that of bupropion, respectively. The hepatic clearance in patients with liver disease was increased from 19 to 29 hours. The median observed tm ax was 19 hours for hydroxybupropion and 31 hours for threo/erythro-hydrobupropion. The mean half-lives for hydroxybupropion and threo/erythro-hydrobupropion were increased by five- and two times, respectively, in patients with severe hepatic cirrhosis compared with healthy volunteers Bupropion and its metabolites are distributed into breast milk.

Clinical Use

Wellbutrin and Zyban (an aid in smoking cessation treatment) are trade name products for bupropion. Therefore, the potential exists for an overdose toxicity in a patient receiving multiple brand name and generic prescriptions containing bupropion for the treatment of depression, smoking cessation, and other off-label uses.
Besides being used to treat depression, bupropion is a nonnicotine aid in the cessation of smoking. The efficacy of bupropion in smoking cessation is comparable to that of nicotine replacement therapy and should be considered as a second-line treatment in smoking cessation. It possesses a broad spectrum of infrequent adverse effects, however, with potential drug metabolism interactions with TCAs, β-adrenergic blocking drugs, and class Icantiarrhythmics.

Enzyme inhibitor

This β-ketoamphetamine-type antidepressant and smoking cessation aid (FW = 239.74 g/mol; CAS 34841-39-9), also known as Wellbutrin?, Zyban?, and (±)-2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-one, is said to be a norepinephrine and dopamine reuptake inhibitor, although its weak effect on dopamine levels calls into question the latter action. Bupropion also acts noncompetitively as a neuronal acetylcholine receptor antagonist. Unlike many antidepressants, however, bupropion shows no serotonergic activity. It also lacks typical antidepressant side effects, e.g., sexual dysfunction, weight gain, and sedation. Pharmacokinetics: Upon oral administration, bupropion is rapidly absorbed with first-order kinetics and subsequently eliminated via biphasic kinetics, with a redistribution t1/2 of ~1 hour and an elimination t1/2 of 11-14 hours. Widely distributed throughout the body, bupropion is extensively metabolized, both oxidatively and reductively, to form as many as six metabolites, of which some are pharmacologically active. While bupropion does not inhibit monoamine oxidase, it exerts no effect on serotonin uptake. It minimally alters the reuptake of norepinephrine at presynaptic sites. Importantly, bupropion does not act on postsynaptic b-adrenergic down-regulation or presynaptic dopamine uptake. Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics. Key Pharmacokinetic Parameters: See Appendix II in Goodman & Gilman’s THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, 12th Edition (Brunton, Chabner & Knollmann, eds.) McGraw-Hill Medical, New York.

Drug interactions

Inhibition studies with the SSRIs and bupropion suggest that bupropion is a potent CYP2D6 inhibitor. Bupropion hydroxylation was strongly inhibited by, in the following order, paroxetine> fluvoxamine> sertraline> desmethylsertraline> norfluoxetine> nefazodone> fluoxetine and only weakly inhibited by venlafaxine, ODV, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by SSRIs suggests the potential for clinical drug interactions. Therefore, coadministration of drugs that inhibit CYP2D6 warrants careful monitoring. Because of its selective inhibition of DA reuptake, pharmacodynamic interactions with dopamine agonists (e.g., levodopa) and antagonists should be anticipated. Coadministration of bupropion with drugs that lower the seizure threshold should be avoided because of the risk of serious seizures.
Drugs that affect metabolism by CYP2B6 also have the potential to interact with bupropion.

Bupropion(34841-39-9)Related Product Information

• tert-Butyldimethylsilyl chloride
• tert-Butylbenzene
• Methyl 4-tert-butylbenzoate
• Propane
• tert-Butyl methyl ether
• 2-tert-Butylphenol
• 4-tert-Butylcatechol
• 4-tert-Butylphenol
• tert-Butylchlorodiphenylsilane
• tert-Butyl hydroperoxide
• tert-Butanol
• Bupropion hydrochloride
• Hydroxybupropione
• BUPROPION-D9
• Bupropion