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Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Several metabolites of bupropion are pharmacologically active and have longer half-lives, and achieve higher plasma concentrations, than the parent compound. Hydroxybupropion is the major metabolite, produced by the metabolism of bupropion by the cytochrome P450 isoenzyme CYP2B6; in animal studies hydroxybupropion was one-half as potent as bupropion. Threohydrobupropion and erythrohydrobupropion are produced by reduction and are about one-fifth the potency of the parent compound.
Practice patterns of bupropion co-prescription with antipsychotic medications
Published in Journal of Addictive Diseases, 2022
Mohan Gautam, Shivali Patel, Paul Zarkowski
After oral administration, bupropion undergoes extensive first pass metabolism.14 The three major metabolites are hydroxybupropion, erythrohydrobupropion, and threohydrobupropion.12 The plasma concentration of erythrohydrobupropion is exceedingly limited compared to the plasma concentration of the other metabolites. Whereas threohydrobupropion and bupropion plasma concentrations are similar, the concentration of hydroxybupropion is up to five times higher than either of them. This observation is most pronounced in the extended release formulation.12,13,15,16
Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects
Published in Drug Metabolism Reviews, 2019
Rafaela Costa, Nuno G. Oliveira, Ricardo Jorge Dinis-Oliveira
Since its introduction in the market in 1989, bupropion has been proposed for several clinical conditions, namely depression and in the treatment of smoking cessation aid. However, with over 40 million patients worldwide prescribed with bupropion (Fava et al. 2005), understanding the possible causes of intersubject complex pharmacokinetic and pharmacodynamic variability is critical to assure safety and efficacy. Figure 3 highlights major clinical, pharmacokinetic and pharmacodynamic aspects of bupropion. Bupropion is a synthetic cathinone that exerts its effects through inhibition of dopamine, noradrenaline reuptake and inhibition of nicotinic receptors (Damaj et al. 2004; Shalabi et al. 2017). Bupropion is cleared via oxidation by cytochrome P450 to hydroxybupropion and 4’-hydroxybupropion and via reduction by 11β-HSD-1 and aldoketoreductase to threohydrobupropion and erythrohydrobupropion. All four metabolites undergo glucuronidation, and threo- and erythrohydrobupropion are also hydroxylated to threo-4’-hydroxy- and erythro-4’-hydroxy-hydrobupropion (Gufford et al. 2016; Sager et al. 2016a, 2016b, 2017). The metabolic polymorphic pathway of bupropion is considered crucial to explain the interindividual and interspecies variability in dose-response. Indeed, bupropion exerts antidepressant effects in a mouse model (Musso et al. 1993), which metabolizes bupropion mainly to hydroxybupropion, but it is incapable of exerting that effect in rat models (Welch et al. 1987), which metabolizes bupropion mainly by side-chain cleavage. Hydroxybupropion was thought to be the major active metabolite since the early published reports, being thus extensively studied. However, information available about the pharmacological effects of threohydrobupropion and erythrohydrobupropion, the two other active metabolites of bupropion is scarce. Therefore, dosing bupropion and its metabolites and genotyping metabolizing enzymes and pharmacological targets (Swan et al. 2005; Swan et al. 2007; Choi and Shin 2015) might have a role in the future to evaluate the patient’s response to bupropion. Given bupropion instability in biological samples (Laizure and DeVane 1985), toxicological analysis must target both bupropion and its major metabolites. It is also important to be aware of the chiral inversion of bupropion stereoisomers that may confound some in vitro to in vivo extrapolations. However, this artifact proved to have a minor influence in altering in vivo bupropion R/S ratios dependent on the CYP2B6 activity (Sager et al. 2016b). Due to the bioactive enantiomer’s differences, a stereoselective bioanalytical method for bupropion, hydroxybupropion, erythrohydrobupropion, and threohydrobupropion was recently validated (Teitelbaum et al. 2016a, 2016b). Further studies concerning bupropion HBr are also needed to clarify the implication in the bromism, a toxic syndrome characterized by neurologic, psychiatric and dermatologic adverse effects, when high amounts of bromide are ingested (Bowers and Onoroski 1990; Shader 2009).