Hydroxybupropion

Hydroxybupropion
Clinical data
Other namesBW 306U; 6-Hydroxybupropion
ATC code
  • None
Pharmacokinetic data
Elimination half-life15–25 hours
Identifiers
  • (±)-1-(3-Chlorophenyl)-2-[(1-hydroxy-2-methyl-2-propanyl)amino]-1-propanone
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC13H18ClNO2
Molar mass255.74 g·mol−1
3D model (JSmol)
  • O=C(c1cc(Cl)ccc1)C(NC(C)(C)CO)C
  • InChI=1S/C13H18ClNO2/c1-9(15-13(2,3)8-16)12(17)10-5-4-6-11(14)7-10/h4-7,9,15-16H,8H2,1-3H3
  • Key:AKOAEVOSDHIVFX-UHFFFAOYSA-N

Hydroxybupropion (code name BW 306U), or 6-hydroxybupropion, is the major active metabolite of the antidepressant and smoking cessation drug bupropion.[1] It is formed from bupropion by the liver enzyme CYP2B6 during first-pass metabolism.[1] With oral bupropion treatment, hydroxybupropion is present in plasma at area under the curve concentrations that are as many as 16 to 20 times greater than those of bupropion itself,[1][2] demonstrating extensive conversion of bupropion into hydroxybupropion in humans.[1] As such, hydroxybupropion is likely to play a very important role in the effects of oral bupropion, which could accurately be thought of as functioning largely as a prodrug to hydroxybupropion.[1]

Hydroxybupropion has two chiral centers and is a mixture of four possible enantiomers.[3][4][5] In humans however, presumably due to steric hindrance, only (2R,3R)-hydroxybupropion and (2S,3S)-hydroxybupropion are formed.[3][4][5]

Other metabolites of bupropion besides hydroxybupropion include threohydrobupropion and erythrohydrobupropion.[6][7]

  1. ^ a b c d e Dwoskin LP (29 January 2014). Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse. Elsevier Science. pp. 177–216. ISBN 978-0-12-420177-4. Archived from the original on 4 June 2020. Retrieved 25 October 2016.
  2. ^ Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 612–. ISBN 978-1-60913-345-0. Archived from the original on 11 December 2021. Retrieved 25 October 2016.
  3. ^ a b Carroll FI, Blough BE, Mascarella SW, Navarro HA, Lukas RJ, Damaj MI (2014). "Bupropion and bupropion analogs as treatments for CNS disorders". Adv Pharmacol. 69: 177–216. doi:10.1016/B978-0-12-420118-7.00005-6. 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.
  4. ^ a b 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].
  5. ^ a b 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).
  6. ^ Costa R, Oliveira NG, Dinis-Oliveira RJ (August 2019). "Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects". Drug Metabolism Reviews. 51 (3): 293–313. doi:10.1080/03602532.2019.1620763. PMID 31124380. S2CID 163167323.
  7. ^ Cite error: The named reference Jefferson_2005 was invoked but never defined (see the help page).