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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).
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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.
The role of xenobiotic-metabolizing enzymes in the placenta: a growing research field
Published in Expert Review of Clinical Pharmacology, 2020
Ricardo Blanco-Castañeda, Carlos Galaviz-Hernández, Paula C. S. Souto, Victor Vitorino Lima, Fernanda R. Giachini, Carlos Escudero, Alicia E Damiano, L. Jazel Barragán-Zúñiga, Gerardo Martínez-Aguilar, Martha Sosa-Macías
Reports of in vitro and in placental perfusion studies showed that the human placenta metabolizes bupropion to erythro- and threohydrobupropion and in lower amounts to hydroxybupropion [117,118]. These metabolites are pharmacologically less active than bupropion [193,194]. Data from an in vivo study demonstrated that the concentrations of bupropion metabolites in the umbilical cord are higher than those of bupropion [119]. Moreover, higher levels of threohydrobupropion in the amniotic fluid than those in the umbilical cord are found, suggesting that this metabolic pathway is very active in the fetus [119]. In microsomal fractions, 11B-hydroxysteroid dehydrogenases are the main placental enzymes involved in the reduction of bupropion to erythro- and threohydrobupropion, whereas CYP2B6 and, to a lesser extent, CYP19 are responsible for the formation of hydroxybupropion [117]. Bupropion metabolites increase significantly (p < 0.01) in the placentas of women who smoked >20 cigarettes per day compared to metabolites in placentas of nonsmokers [117]. A placental perfusion study showed that threohydrobupropion and bupropion at concentrations 150 ng/mL and 450 ng/mL did not affect the placental tissue viability or the functional parameters [118]. Bupropion administration during pregnancy has been related to low risk of teratogenicity but it is associated with left ventricular outflow tract obstruction when bupropion is administrated during the first trimester of gestation [195].
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
The recent work of Masters et al (2016a) has clearly delineated the complex stereoselective metabolism of bupropion leading to chiral primary and secondary metabolites (Masters et al., 2016a). The distinctive PK profiles of the various chiral moieties of parent drug and metabolites were well documented (Masters et al., 2016a). A pronounced stereoselectivity was observed in the plasma concentration profile for parent drug (R-bupropion > S-bupropion; AUCinf ratio: 6.0) and key metabolites such as hydroxybupropion (R,R > S,S; AUCinf ratio:65), erythrohydrobupropion (S,R > R,S; AUCinf ratio: 6.4) and threohydrobupropion (R,R > S,S; AUCinf ratio: 2.9) (Masters et al., 2016a). The apparent body clearance and volume of distribution parameters were found to be 3.7 to 6-times greater for S-bupropion relative to R-bupropion (Masters et al., 2016a). In terms of time to peak concentration, stereoisomeric pairs of the parent bupropion and two active metabolites had similar values; with the exception of threohydrobupropion, where R,R-diasteromer had a prolonged value as compared to the S,S-diasteromer (Masters et al., 2016a). The disposition in particular observed for threohydrobupropion diastereomers was worth noting. During the initial 6 h after bupropion dosing, the S,S-threohydrobupropion concentrations were greater compared to the R,R-threohydrobupropion; however, beyond, 6 h there appeared to be a reversal in the plasma profiles suggesting site specific formation of the two diasteromers (Masters et al., 2016a). Based on the t1/2 values of the individual enantiomers of bupropion metabolites, it appeared that one of the stereoisomeric form of each pair of active metabolite had a longer residence in the circulation. Hence, during chronic therapy of bupropion, accumulation of metabolites in a stereoselective fashion needs to be expected. As a part of the exercise, Masters et al. (2016a, 2016b) simulated the steady state PKs for the stereoisomers of bupropion and active metabolites (Masters et al., 2016a). Accordingly, enantiomers of bupropion and the enantiomers of various active metabolites showed accumulation indices ranging from 1.6 to 6. The highest accumulation index of 6 was observed for the R,R-threohydrobupropion and the accumulation of the parent enantiomers ranged between 1.7 and 2 (Masters et al., 2016a).
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).