China
Africa
Explore chapters and articles related to this topic
Inhibitors of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Both bupropion and hydroxybupropion inhibit CYP2D6-mediated dextromethorphan O-demethylation, with IC50 values of 58 and 74 μM, respectively (Figure 4.5) (Hesse et al. 2000). When bufuralol is used as a probe in human liver microsomes, the two metabolites of bupropion (erythrohydro-bupropion and threohydrobupropion) are more potent inhibitors of CYP2D6 activity (Ki = 1.7 and 5.4 μM, respectively) than hydroxybupropion (Ki = 13 μM) or bupropion (Ki = 21 μM) (Reese et al. 2008). Bupropion increases the AUC of desipramine fivefold in humans (Reese et al. 2008).
B
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.
Norepinephrine in Depression and Anxiety
Published in Siegfried Kasper, Johan A. den Boer, J. M. Ad Sitsen, Handbook of Depression and Anxiety, 2003
Like other tricyclic antidepressants, it has a host of pharmacological properties that contribute to its side-effect burden. These include anticholinergic, antihistaminergic, and anti-adrenergic effects [134]. Desipramine has been reported to be effective in the treatment of panic disorder [135-138], although clomipramine was even more effective [138]. Desipramine is not efficacious in treatment of OCD [139-141], or post-traumatic stress disorder (PTSD) [142,143]. Bupropion is a very weak DA reuptake blockade inhibitor; its behavioral profile in laboratory animals and humans is that of a central nervous system (CNS) stimulant and indirect DA agonist [144]. It increases locomotor activity and causes stereotyped behaviors in laboratory animals. In humans, it can cause restlessness, insomnia, anorexia, and psychosis. Bupropion is structurally related to phenylethylamines and unrelated to the TCAs, SSRIs, or MAOIs. It has no significant potency at binding to any known neurotransmitter receptors. It has no significant effects at blocking reuptake of 5HT or NA, although its primary metabolite (hydroxybupropion) is a potent NA reuptake inhibitor [145]. Hydroxybupropion is produced rapidly in humans, with peak plasma levels of up to 3 times those of bupropion and a half-life of 24. Clinical studies have demonstrated that bupropion is effective in the treatment of major depressive episodes [134]. While early studies suggested that bupropion might be less likely to cause hypomania or mania in bipolar patients, subsequent studies suggested that it can cause mania and psychosis in bipolar patients, especially those with high pretreatment levels of the DA metabolite HVA [146,147]. In a recent open-label study, bupropion was not effective for treatment of PTSD [148]. However, contrary to commonly held clinical impressions, bupropion was reported to have therapeutic effects in a patient with social phobia [149]. Additionally, a recent review contrasting the relative efficacy of bupropion and sertraline in treatment of anxiety symptoms in patients with major depression showed that baseline Hamilton Anxiety Scale (Ham-A) scores did not predict response to either drug [150] and both drugs equally reduced Ham-A total score [151].
Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion
Published in Xenobiotica, 2018
Ranjeet Prasad Dash, Rana Rais, Nuggehally R. Srinivas
Preclinical research has revealed that bupropion augments monoaminergic neurotransmission differently from other antidepressants (Ferris & Cooper, 1993). Studies in rats and mice suggested that bupropion and its metabolites such as hydroxybupropion, threohydrobupropion (Figure 1) and erythrohydrobupropion (Figure 1) did not amend serotonergic neurotransmission either presynaptically (by affecting serotonin release or reuptake) or postsynaptically (by binding to serotonin receptors) (Ascher et al., 1995; Ferris et al., 1993). Instead bupropion and hydroxybupropion, reduced the reuptake of dopamine and norepinephrine into rat and mouse synaptosomes. Furthermore, bupropion diminished the sacking of dopamine and norepinephrine neurons in the brain stems of rats in a dose-dependent pattern (Ascher et al., 1995; Ferris et al., 1993). This effect was consistent with an elevation in synaptic levels of dopamine and norepinephrine which subsequently impeded neuronal firing via an autoreceptor-mediated negative feedback mechanism (Stahl et al., 2004). Clinical studies exhibited decreased whole-body turnover of norepinephrine without altering plasma norepinephrine levels, thus suggesting significant central noradrenergic activity (Golden et al., 1988a).
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).