Bupropion is substantially converted into metabolites duringfirst-pass metabolism withoral administration and levels of its metabolites are much higher than those of bupropion itself.[1][5] Exposure to (2R,3R)-hydroxybupropion is 29-fold higher than to (R)-bupropion and exposure to (2S,3S)-hydroxybupropion is 3.7-fold higher than to (S)-bupropion.[5] Other metabolites that circulate at higher concentrations than those of bupropion includethreohydrobupropion and to a lesser extenterythrohydrobupropion.[1][5]
Themetabolism of bupropion and its metabolites isstereoselective.[4][5] During bupropion therapy, exposure to (R)-bupropion is 2- to 6-fold higher than to (S)-bupropion and exposure to (2R,3R)-hydroxybupropion is 20- to 65-fold higher than to (2S,3S)-hydroxybupropion.[4][2][5] Hence, (2R,3R)-hydroxybupropion is a major metabolite of bupropion and (2S,3S)-hydroxybupropion is a minor metabolite.[4][2][5]
In contrast to humans, only low levels of hydroxybupropion or (2R,3R)-hydroxybupropion occur with bupropion in rats.[3][4] This highlights substantial species differences in thepharmacokinetics of bupropion between animals and humans.[3][4][1] These differences in turn may account for differences in thepharmacodynamic effects of bupropion between species.[3][4][1]
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site.
Additional studies have characterized theaffinities (Ki) of bupropion and the hydroxybupropion enantiomers at the monoamine transporters as well as affinities and potencies (IC50) using non-human proteins.[13] In contrast to bupropion and (2S,3S)-hydroxybupropion, racemic hydroxybupropion, using rat proteins, has been found to act as aselectivenorepinephrine reuptake inhibitor (IC50 = 1,700nM) with no apparent inhibition of dopamine reuptake (IC50 > 10,000nM).[6] Normally, activity with racemic mixtures is expected to be closer to that of the active enantiomer than to the inactive enantiomer.[6] The reasons for the discrepancy in the case of racemic hydroxybupropion are unclear.[6] In any case, it was suggested that (2R,3R)-hydroxybupropion might be acting as a negative allosteric modulator of the binding of (2S,3S)-hydroxybupropion to thedopamine transporter.[6]
Bupropion and (2S,3S)-hydroxybupropion are substantially more potent than (2R,3R)-hydroxybupropion in variousrodent behavioral tests, such as theforced swim test (an assay of antidepressant-like activity).[4][1][6][7][8] However, sufficient doses of bupropion, (2S,3S)-hydroxybupropion, and (2R,3R)-hydroxybupropion all produce fullmethamphetamine-like effects in monkeys (1mg/kg, 3mg/kg, and 10mg/kg, respectively).[14][15] Bupropion producesnicotine-like effects in rodents and (2S,3S)-hydroxybupropion partially substitutes for nicotine.[3] In contrast, (2R,3R)-hydroxybupropion does not substitute for nicotine and dose-dependently antagonizes the effects of nicotine by up to 50%.[3]
(2R,3R)-Hydroxybupropion is a strongCYP2D6inhibitor similarly to bupropion.[1][2] (2R,3R)-Hydroxybupropion alone has been estimated to account for approximately 65% of the totalin vivo CYP2D6 inhibition of bupropion, whereasthreohydrobupropion accounted for 21% anderythrohydrobupropion accounted for 9% (with 5% remaining or unaccounted for).[2]
CYP2B6 is highlypolymorphic and is subject to highinterindividual variability of approximately 100-fold.[1] This may result in large interindividual differences in the metabolism of bupropion into hydroxybupropion and the effects of bupropion.[1] However,clearance of bupropion is not affected in different CYP2B6 metabolizer phenotypes.[1] This suggests that other enzymes compensate in the metabolism of bupropion in the context of reduced CYP2B6 function.[1] The moderate CYP2B6inducerrifampicin increased the clearance of (2R,3R)-hydroxybupropion and decreased its exposure and half-life by approximately 50%.[2]
^abcdefghijklmnopqrCosta R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects".Drug Metab Rev.51 (3):293–313.doi:10.1080/03602532.2019.1620763.PMID31124380.
^abcdefghijklDash RP, Rais R, Srinivas NR (September 2018). "Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion".Xenobiotica.48 (9):945–957.doi:10.1080/00498254.2017.1376765.PMID28876959.
^abcdefghijklmnopqrCarroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders".Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Adv Pharmacol. Vol. 69. pp. 177–216.doi:10.1016/B978-0-12-420118-7.00005-6.ISBN978-0-12-420118-7.PMID24484978.The hydroxylation of bupropion to form hydroxybupropion occurs by cytochrome P450 2B6 (CYP2B6) oxidation (Faucette et al., 2000; Faucette, Hawke, Shord, Lecluyse, & Lindley, 2001; Hesse et al., 2000), and the subsequent cyclization results in the creation of a second chiral center with the potential for the generation of two diastereomers (Suckow, Zhang, & Cooper, 1997). Interestingly, only the trans-diastereomers, (2S,3S)- and (2R,3R)-hydroxybupropion (2a and 2b, respectively), have been found in plasma in humans and when synthesized de novo (Fang et al., 2000), indicating that they are the thermodynamically more stable isomers. Steric hindrance greatly reduces cyclization to the cis-diastereomers, (2R,3S)- and (2S,3R)-hydroxybupropion (Suckow et al., 1997). The chirality of the second stereocenters is determined by the configuration of the existing stereocenter alpha to the ketone derived from either (S)- or (R)- bupropion.
^abcdefghiKharasch ED, Neiner A, Kraus K, Blood J, Stevens A, Miller JP, Lenze EJ (November 2020). "Stereoselective Steady-State Disposition and Bioequivalence of Brand and Generic Bupropion in Adults".Clin Pharmacol Ther.108 (5):1036–1048.doi:10.1002/cpt.1888.PMID32386065.
^abcdefghijkDamaj MI, Carroll FI, Eaton JB, Navarro HA, Blough BE, Mirza S, Lukas RJ, Martin BR (September 2004). "Enantioselective effects of hydroxy metabolites of bupropion on behavior and on function of monoamine transporters and nicotinic receptors".Mol Pharmacol.66 (3):675–682.doi:10.1124/mol.104.001313.PMID15322260.
^Eshleman AJ, Carmolli M, Cumbay M, Martens CR, Neve KA, Janowsky A (May 1999). "Characteristics of drug interactions with recombinant biogenic amine transporters expressed in the same cell type".J Pharmacol Exp Ther.289 (2):877–885.doi:10.1016/S0022-3565(24)38214-X.PMID10215666.
^Nelson DL, Gehlert DR (February 2006). "Central nervous system biogenic amine targets for control of appetite and energy expenditure".Endocrine.29 (1):49–60.doi:10.1385/endo:29:1:49.PMID16622292.
^abcNiemegeers P, Dumont GJ, Patteet L, Neels H, Sabbe BG (September 2013). "Bupropion for the treatment of seasonal affective disorder".Expert Opin Drug Metab Toxicol.9 (9):1229–1240.doi:10.1517/17425255.2013.804062.PMID23705752.As hydroxybupropion has two chiral centers, there are four possible enantiomers. However, only (R,R)-hydroxybupropion and (S,S)-hydroxybupropion are found in human plasma [62].
^abcEap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C (October 2021). "Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants".World J Biol Psychiatry.22 (8):561–628.doi:10.1080/15622975.2021.1878427.hdl:11250/2981927.PMID33977870.Bupropion is chiral and CYP2B6 stereoselective metabolism is observed with (S)-bupropion being metabolised at more than three times the rate of (R)-bupropion (Coles and Kharasch 2008). Because hydroxybupropion has two chiral centres, four enantiomers should be observed: however, only (R,R)-hydroxybupropion and (S,S)- hydroxybupropion are found (Coles and Kharasch 2008).
^Batra S, Bhushan R (May 2016). "Resolution of enantiomers of bupropion and its metabolites by liquid chromatography".Biomed Chromatogr.30 (5):670–682.doi:10.1002/bmc.3572.PMID26230937.S,S)- and (R,R)-hydroxybupropion have been found in plasma in humans, presumably owing to steric hindrance precluding formation of (R,S)- and (S,R)-hydroxybupropion.
-Hydroxybupropion.svg)
