Bupropion development

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. 

One of the metabolites of bupropion, radafaxine (GW 353162, 25), is being studied as a treatment for obesity in clinic trials [76]. It is also reported to be in clinical development for restless leg syndrome, neuropathic pain, bipolar disorder and fibromyalgia [68]. 

This report presents various methods developed primarily at our laboratory for chromatographic resolution of racemates of several pharmaceuticals (e.g., -blockers, NSAIDS, anta-acids, DL-amino acids, Bupropion, Baclofen, Etodolac, Carnitine, Mexiletine). Recently, we developed methods for establishing molecular dissymmetry and determining absolute configuration of diastereomers (and thus the enantiomers) of (/< .S )-Baclofcn, (/d.SJ-Bctaxolol with complimentary application of TLC, HPLC, H NMR, LCMS this ensured the success of diastereomeric synthesis and the reliability of enantioseparation. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Use caution in patients with a recent history of Ml or unstable heart disease. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants and was generally well tolerated in depressed patients with stable CHF. Bupropion was associated P.784... 

Bupropion belongs to the chemical class of aminoketones. It is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist. Initially developed and marketed as an antidepressant, bupropion was subsequently found to be effective as a smoking cessation aid. If given to lactating women it can trigger convulsions in the newborn. 

Bupropion was developed over 30 years ago in an attempt to synthesize a novel antidepressant. Researchers wanted the agent to be efficacious for the existing screening models, but be different structurally and biochemically from the tricyclics and MAOIs. The compound was to be devoid of sympathomimetic, anticholinergic, and cardiac depressant effects (Soroko and Maxwell, 1983). 

The role of dopamine is discussed more thoroughly in Finder, Chapter 14, in this volume. Several antidepressants are thought to have enhanced antidepressant action attributed to extra effects on the dopamine system. Bupropion, which is available as an antidepressant in the United States only, has an indirect effect on dopamine. An appropriate minimum effective dose was not established in the early clinical trial development program, and the rather high doses used in clinical practice may have contributed to the number of reports of convulsions. The rate, which is acceptable at lower doses of 450 mg/day, rises to unacceptable levels at higher doses [J. A. Johnston et al. 1991). 

Thus, the clinician might use TDM with bupropion to guard against the development of unusually high plasma levels of the parent drug or its metabolites. That would be particularly true for the medically compromised or the patient on other drugs that could interfere with the clearance of bupropion. In such a case, the laboratory should assay the parent drug and its three major metabolites—hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. 

Because reboxetine and bupropion share with desipramine the ability to block the NE uptake pump, some clinician may want to combine them with an SSRI. Bupropion, however, should be used cautiously with fluvoxamine, fluoxetine, and paroxetine because these three antidepressants inhibit one or more CYP enzymes to a substantial degree at their lowest, usually effective antidepressant dose. Therefore, the dose of bupropion should be kept low and TDM could be used to ensure that unusually high levels of bupropion or its active metabolites do not develop. 

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. 

Wellbutrin and Zyban are marketed as a racemic mixture of bupropion as its hydrochloride salt. However, over the past 15 years there has been an increasing trend to develop new drugs as single enantiomers. Several publications have demonstrated that the enantiomers of many chiral compounds have distinct pharmacological profiles and the benefits in using a single enantiomer over the racemate... 

Extensive studies on bupropion, including animal models of depression, have demonstrated that the desired inhibition of dopamine and norepinephrine reuptake resides mainly with radafaxine (that is the (S,S)-enantiomer, 2a). Furthermore, these studies confirmed that the (R,R) -enantiomer, 2b, is associated with a number of the known related undesirable side effects. Hence, development of radafaxine hydrochloride was undertaken for the treatment of Major Depressive Disorder (MDD) as a stand-alone New Chemical Entity (NCE). Furthermore, owing to the undesirable side effects associated with the (R,R)-enantiomer 2b, levels of this compound were to be controlled to <0.5% to minimize these effects. 

The noradrenaline and dopamine reuptake inhibitor bupropion (GlaxoSmithKline) is currently in clinical development (phase II) for neuropathic pain. 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

A 35-year-old woman with no history of a psychiatric disorder was given bupropion 300 mg/day for smoking cessation (24). After 5 days she developed an acute paranoid state with ideas of reference and fixed convictions concerning her partner s fidelity. She was also irritable and slightly grandiose. Bupropion was withdrawn and she was given benzodiazepines. She recovered over the next 2 days. 

A 49-year-old woman, who was taking oxcarbazepine for bipolar disorder, developed hyponatremia after also taking bupropion (25). 

For the patient with persistent depressive symptoms, antidepressants are often necessary. However, the possibility of triggering a "switch" into mania must always be considered. Attempts have been made to develop reliable recommendations for the predictive risk of antidepressant-induced mania or hypomania (Kupfer, Carpenter, and Frank 1988, Altshuler et al. 1995). Stoll and colleagues (1994) report less risk with monoamine oxidase inhibitors or bupropion than with tricyclics or serotonin specific antidepressants. Due to lack of controlled studies and heterogeneous data sources, this issue remains controversial and is far from resolved. 

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