Bupropion metabolism

A few cases have been reported suggesting that bupropion metabolism might be inhibited by fluoxetine, which could eventually lead to abrupt emergence of psychosis and seizure disorder. 

A study found that the AUC of hydroxybupropion, an active metabolite of bupropion, almost doubled when bupropion was given with valproate at steady-state, but the pharmacokinetics of the parent compound and the two other less active metabolites were unaffected. An increase in valproate levels of almost 30% was seen in another report in one patient. Visual and auditory hallucinations were reported in a patient given bupropion and valproate. The UK manufacturer recommends caution when using drugs which may inhibit bupropion metabolism, such as valproate. As valproate levels may also be increased by bupropion, good monitoring for evidence of increased adverse effects of both drugs would seem appropriate. 

Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol (1995) 15, 327-33. 

Sridar C, Kenaan C, Hollenberg PF (2012) Inhibition of bupropion metabolism by selegiline mech-... 

Ilic K, Hawke RL, Thirumaran RK, Schuetz EG, Hull JH, Kashuba AD, Stewart PW, Lindley CM, Chen ML (2013) The influence of sex, ethnicity, and CYP2B6 genotype on bupropion metabolism as an index of hepatic CYP2B6 activity in humans. Drug Metab Dispos 41 575-581... 

Isolated seizures that are not epilepsy can be caused by stroke, central nervous system trauma, central nervous system infections, metabolic disturbances (e.g., hyponatremia and hypoglycemia), and hypoxia. If these underlying causes of seizures are not corrected, they may lead to the development of recurrent seizures I or epilepsy. Medications can also cause seizures. Some drugs that are commonly associated with seizures include tramadol, bupropion, theophylline, some antidepressants, some antipsy-chotics, amphetamines, cocaine, imipenem, lithium, excessive doses of penicillins or cephalosporins, and sympathomimetics or stimulants. 

Metabolism/Excretion- Bupropion is extensively metabolized in the liver. Steady-state plasma concentrations of bupropion and its metabolites are reached within 5 and 8 days, respectively. 

Drugs that may be affected by bupropion include alcohol, drugs metabolized by... 

Pharmacokinetics Following oral administration to healthy volunteers, mean peak plasma concentrations were achieved within 3 hours. Bupropion is 84% bound to human plasma proteins in vitro. Bupropion is extensively metabolized with a mean... 

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In particular, certain drugs may induce the metabolism of bupropion (eg, carbamazepine, phenobarbital, phenytoin) while other drugs may inhibit the metabolism of bupropion (eg, cimetidine, ritonavir). 

In 1986, just prior to its release, seizures were reported in a small number of nondepressed, bulimic patients taking bupropion. Bupropion was removed from the market by the manufacturer until it was determined that seizures in this vulnerable population appeared to be related to high doses (>450 mg) of bupropion used in the context of metabolic instability. The drug was finally released in the United States in 1989. 

Bupropion is an aminoketone that exerts its therapeutic effect through the inhibition of norepinephrine and dopamine reuptake. Bupropion s receptor occupancy profile shows an absence of anticholinergic and antihista-minic effects (Cusack et ah, 1994). Bupropion is absorbed rapidly from the gastrointestinal tract, and peak blood levels are achieved within 2 hours for regular release and 3 hours for sustained-release preparations = 10 hours). Bupropion undergoes extensive first-pass metabolism in the liver, yielding three active metabolites hydrobupropion, threohydroxybu-propion, and erythrohydrobupropion. The half-lives of the active metabolites are approximately 20 + hours (Preskorn, 1993). 

Because bupropion is metabolized in the liver, medications that alter hepatic enzyme metabolism, such as carbamazepine or cimetidine, may effect blood concentrations. Bupropion should not be administered in combination with the MAOIs because of risk of hypertensive crisis. Levo-dopa use in conjunction with bupropion has been associated with confusion, hallucinations, and dyskinesia. Although generally well tolerated, there are case reports documenting that the... 

One of the more worrisome adverse effects of bupropion is seizures. At dosages of 450 mg/day or less, the rate of seizures is 0.4% for individuals without risk factors (Davidson, 1989). Because of this risk, a single dose of bupropion should not exceed 150 mg and a second dose should be separated in time by a minimum of 8 hours. Also, patients who are metabolically unstable (i.e., have bulimia) should be carefully assessed for the risk of seizures before initiating medication. Finally, bupropion is not associated with sexual side effects. 

This lack of information may well relate to bupropion s complex metabolism, whereby biologically active metabolites predominate several-fold over the parent compound these metabolites may ultimately prove to be the basis for therapeutic effects [Golden et al. 1988]. Furthermore, because the full spectrum of action of the metabolites has not been explored, it is difficult to confidently characterize the primary biochemical action of bupropion as noradrenergic. One must therefore be cautious in interpreting any distinct aspects of bupropion s clinical actions as reflecting some noradrenergic mechanisms. And to our knowledge, bupropion is unique in that no other compound available for use in humans has a similar overall profile of preclini-cal and clinical biochemical effects. 

In vitro data suggest that bupropion is metabohzed by CYP 2B6. Bupropion inhibits CYP 2D6. Because of the risk of dose-dependent seizures, caution is warranted when bupropion is combined with other medications that might inhibit its metabolism. 

In contrast to anticonvulsants and alcohol, drugs such as bupropion, fluoxetine, fluvoxamine, nefazodone, quinidine, paroxetine, and some antipsychotics can inhibit specific CYP enzymes (7, 11, 36, 37, 41, 42, 43 and 44). Thus, TCAs, certain BZDs, bupropion, some steroids, and antipsychotics can all have their metabolism inhibited by drugs such as fluoxetine. For example, fluoxetine at 20 mg/day produces on average a 500% increase in the levels of coprescribed drugs which are principally dependent on CYP 2D6 for their clearance. That can lead to serious or even life-threatening toxicity if the drug has a narrow therapeutic index and the dose is not adjusted for the change in clearance caused by the coadministration of fluoxetine. 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

The dearth of information on the metabolism of bupropion may initially seem surprising however, this drug is one of the oldest of the newer antidepressants, having entered clinical trials in the mid-1970 s and having been approved before fluoxetine ( 308, 314, 315). Ironically, its marketing was delayed after its approval because of the risk of seizures, which, in turn, is almost undoubtedly a consequence of its complicated pharmacokinetics ( 163). 

Davidson (426) found that the risk of seizures with bupropion was higher at doses greater than the recommended maximum (i.e., 450 mg per day). The seizure risk may be as low as one per 1,000 patients with the sustained release formulation when the dose is kept less than 450 mg per day, and the patient has no preexisting seizure history and is not on any medication that also can lower seizure thresholds or interfere with the metabolism of bupropion. 

Three randomized clinical trials support the efficacy of bupropion in ADHD. The first used doses up to 6 mg/kg (98) the other two used doses of 100 to 300 mg per day in equally divided daily doses spaced at least 6 hours apart ( 99, 100). The concern with bupropion is its seizure risk, which requires that its daily dose stay below 450 mg per day in adults (i.e., approximately 6.5 mg/kg). Virtually no work has been done to determine the plasma concentrations of bupropion and its three active metabolites in children and adolescents. Hence, it is unknown whether a limit of 6.5 mg per kg is also appropriate for children. No data exist as to whether children are more or less sensitive to bupropion in terms of seizure risk at the same drug concentration. Also, little is known about pharmacokinetic drug-drug interactions that could reduce the clearance of bupropion. For these reasons, cautious dosing is advised when prescribing bupropion for children on other medications that can reduce oxidative drug metabolism (see Chapter 3 and Chapter 7 for more details). 

Bupropion is rapidly absorbed and has a mean protein binding of 85%. It undergoes extensive hepatic metabolism and has a substantial first-pass effect. It has three active metabolites including hydroxybupropion the latter is being developed as an antidepressant. Bupropion has a biphasic elimination with the first phase lasting about 1 hour and the second phase lasting 14 hours. 

Bupropion is metabolized primarily by CYP2B6, and its metabolism may be altered by drugs such as cyclophosphamide, which is a substrate of 2B6. The major metabolite of bupropion, hydroxybupropion, is a moderate inhibitor of CYP2D6 and so can raise desipramine levels. Bupropion should be avoided in patients taking MAOIs. 

Bupropion Increased norepinephrine and dopamine activity Presynaptic release of catecholamines Major depression smoking cessation (bupropion) sedation Extensive metabolism in liver Toxicity Lowers seizure threshold (amoxapine,... 

While the amine hypothesis is undoubtedly too simplistic, it has provided the major experimental models for the discovery of new antidepressant drugs. As a result, all the currently available antidepressant drugs—except bupropion—are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonism of serotonin, norepinephrine, or both. 

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