(2R,3R)-Hydroxybupropion

(2R,3R)-Hydroxybupropion
Clinical data
Other names(R,R)-Hydroxybupropion
Pharmacokinetic data
MetabolismGlucuronidation[1][2]
MetabolitesHydroxybupropion glucuronide[1][2]
Elimination half-life19–26 hours[1][2]
Identifiers
  • (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO2
Molar mass255.74 g·mol−1
3D model (JSmol)
  • C[C@@H]1[C@](OCC(N1)(C)C)(C2=CC(=CC=C2)Cl)O
  • InChI=1S/C13H18ClNO2/c1-9-13(16,17-8-12(2,3)15-9)10-5-4-6-11(14)7-10/h4-7,9,15-16H,8H2,1-3H3/t9-,13+/m1/s1
  • Key:RCOBKSKAZMVBHT-RNCFNFMXSA-N

(2R,3R)-Hydroxybupropion, or simply (R,R)-hydroxybupropion, is the major metabolite of the antidepressant, smoking cessation, and appetite suppressant medication bupropion.[3][4][1][5] It is the (2R,3R)-enantiomer of hydroxybupropion, which in humans occurs as a mixture of (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion (radafaxine).[4][5] Hydroxybupropion is formed from bupropion mainly by the cytochrome P450 enzyme CYP2B6.[4][1][2] Levels of (2R,3R)-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy.[4][2][5]

Exposure with bupropion

Bupropion is substantially converted into metabolites during first-pass metabolism with oral 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 include threohydrobupropion and to a lesser extent erythrohydrobupropion.[1][5]

The metabolism of bupropion and its metabolites is stereoselective.[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 the pharmacokinetics of bupropion between animals and humans.[3][4][1] These differences in turn may account for differences in the pharmacodynamic effects of bupropion between species.[3][4][1]

Pharmacology

Pharmacodynamics

(2R,3R)-Hydroxybupropion is much less pharmacologically active as a monoamine reuptake inhibitor than bupropion or (2S,3S)-hydroxybupropion.[4][6][7][8] Conversely, its potency as a negative allosteric modulator of nicotinic acetylcholine receptors is variable but overall more similar to that of bupropion and (2S,3S)-hydroxybupropion.[4][6][7][8]

Bupropion and hydroxybupropion functional activities (IC50) at human biological targets[9][10][11]
Compound Monoamine reuptake inhibition nAChR inhibition Ref
DA NE 5-HT α3β4 α4β2 α4β4 α1β1
Bupropion 660–2,900 1,450–1,850 >10,000–47,000 1,800 12,000 12,000–14,000 7,900 [12][7][6]
(2R,3R)-Hydroxybupropion >10,000 9,900 >10,000 6,500 31,000 41,000 7,600 [7][6]
(2S,3S)-Hydroxybupropion 630 241 >10,000 10,000–11,000 3,300 30,000 28,000 [7][6]
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site.
Bupropion and hydroxybupropion inhibition (IC50, nM) of rat monoamine transporters[6]
Compound DAT NET
Bupropion 550 ± 65 1900 ± 12
(2RS,3RS)-Hydroxybupropion >10000 1700 ± 830
(2S,3S)-Hydroxybupropion 790 ± 11 520 ± 35
(2R,3R)-Hydroxybupropion >10000 >10000
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site.

Additional studies have characterized the affinities (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 a selective norepinephrine reuptake inhibitor (IC50 = 1,700 nM) with no apparent inhibition of dopamine reuptake (IC50 > 10,000 nM).[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 the dopamine transporter.[6]

Bupropion and (2S,3S)-hydroxybupropion are substantially more potent than (2R,3R)-hydroxybupropion in various rodent behavioral tests, such as the forced 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 full methamphetamine-like effects in monkeys (1 mg/kg, 3 mg/kg, and 10 mg/kg, respectively).[14][15] Bupropion produces nicotine-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 strong CYP2D6 inhibitor similarly to bupropion.[1][2] (2R,3R)-Hydroxybupropion alone has been estimated to account for approximately 65% of the total in vivo CYP2D6 inhibition of bupropion, whereas threohydrobupropion accounted for 21% and erythrohydrobupropion accounted for 9% (with 5% remaining or unaccounted for).[2]

Pharmacokinetics

Hydroxybupropion, including both (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion, is mainly formed from bupropion by the cytochrome P450 enzyme CYP2B6.[4][1][2] However, CYP2C19, CYP3A4, CYP1A2, and CYP2E1 appear to play a minor role.[1]

CYP2B6 is highly polymorphic and is subject to high interindividual 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 CYP2B6 inducer rifampicin increased the clearance of (2R,3R)-hydroxybupropion and decreased its exposure and half-life by approximately 50%.[2]

The elimination half-life of (2R,3R)-hydroxybupropion is 19 to 26 hours.[1][2]

Chemistry

Hydroxybupropion has two chiral centers.[4][16][17] As a result, there are four possible enantiomers of the compound.[4][16][17] However, only (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion are formed in humans.[4][16][17] (2R,3S)- and (2S,3R)-Hydroxybupropion do not occur in humans presumably due to steric hindrance precluding their formation.[4][18]

References

  1. ^ a b c d e f g h i j k l m n o p q r Costa 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. PMID 31124380.
  2. ^ a b c d e f g h i j k l Dash 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. PMID 28876959.
  3. ^ a b c d e f Dwoskin LP, Rauhut AS, King-Pospisil KA, Bardo MT (2006). "Review of the pharmacology and clinical profile of bupropion, an antidepressant and tobacco use cessation agent". CNS Drug Rev. 12 (3–4): 178–207. doi:10.1111/j.1527-3458.2006.00178.x. PMC 6506196. PMID 17227286.
  4. ^ a b c d e f g h i j k l m n o p q r Carroll 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. ISBN 978-0-12-420118-7. PMID 24484978. 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.
  5. ^ a b c d e f g h i Kharasch 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. PMID 32386065.
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  7. ^ a b c d e f Lukas RJ, Muresan AZ, Damaj MI, Blough BE, Huang X, Navarro HA, Mascarella SW, Eaton JB, Marxer-Miller SK, Carroll FI (June 2010). "Synthesis and characterization of in vitro and in vivo profiles of hydroxybupropion analogues: aids to smoking cessation". J Med Chem. 53 (12): 4731–4748. doi:10.1021/jm1003232. PMC 2895766. PMID 20509659.
  8. ^ a b c Carroll FI, Muresan AZ, Blough BE, Navarro HA, Mascarella SW, Eaton JB, Huang X, Damaj MI, Lukas RJ (March 2011). "Synthesis of 2-(substituted phenyl)-3,5,5-trimethylmorpholine analogues and their effects on monoamine uptake, nicotinic acetylcholine receptor function, and behavioral effects of nicotine". J Med Chem. 54 (5): 1441–1448. doi:10.1021/jm1014555. PMC 3048909. PMID 21319801.
  9. ^ Liu, Tiqing (4 August 2024). "Binding Database Home". BindingDB. Retrieved 19 August 2024.
  10. ^ "PDSP Database". UNC (in Zulu). Retrieved 19 August 2024.
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  13. ^ 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. PMID 16622292.
  14. ^ Reith ME, Gnegy ME (2020). "Molecular Mechanisms of Amphetamines". Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 258: 265–297. doi:10.1007/164_2019_251. ISBN 978-3-030-33678-3. PMID 31286212.
  15. ^ Banks ML, Smith DA, Blough BE (April 2016). "Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys". Behav Pharmacol. 27 (2-3 Spec Issue): 196–203. doi:10.1097/FBP.0000000000000224. PMC 4779668. PMID 26886209.
  16. ^ a b c Niemegeers 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. PMID 23705752. 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].
  17. ^ a b c Eap 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. PMID 33977870. 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).
  18. ^ 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. PMID 26230937. 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.