This article has multiple issues. Please help improve it or discuss these issues on the talk page. (Learn how and when to remove these template messages) This article needs attention from an expert in Chemicals. The specific problem is: Structure/isometry (see also erythrohydrobupropion). WikiProject Chemicals may be able to help recruit an expert. (August 2022) This article may be too technical for most readers to understand. Please help improve it to make it understandable to non-experts, without removing the technical details. (August 2022) (Learn how and when to remove this message) This article may be very hard to understand. Please help clarify it. (September 2023) (Learn how and when to remove this message)
Threohydrobupropion
Clinical data
Other namesthreo-Hydrobupropion; Threohydroxybupropion; BW 494; BW A494U; threo-3-Chloro-N-tert-butyl-β-hydroxy-α-methylphenethylamine; threo-3-Chloro-N-tert-butyl-β-hydroxyamphetamine
Pharmacokinetic data
Protein binding42%[1]
MetabolismHydroxylation (CYP2B6, CYP2C19), glucuronidation (UGTs)[1]
Elimination half-life37 hours[1][2]
Identifiers
  • 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-ol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.216.731 Edit this at Wikidata
Chemical and physical data
FormulaC13H20ClNO
Molar mass241.76 g·mol−1
3D model (JSmol)
  • CC(C(C1=CC(=CC=C1)Cl)O)NC(C)(C)C
  • InChI=1S/C13H20ClNO/c1-9(15-13(2,3)4)12(16)10-6-5-7-11(14)8-10/h5-9,12,15-16H,1-4H3
  • Key:NDPTTXIBLSWNSF-UHFFFAOYSA-N

Threohydrobupropion (developmental code names BW 494, BW A494U) is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin).[1][2] Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities.[1] Threohydrobupropion exists as two isomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion.[3][1] Other metabolites of bupropion include hydroxybupropion and erythrohydrobupropion.[1][2]

Information on the pharmacological actions of threohydrobupropion is scarce.[1] In any case, it is about 20% as pharmacologically potent as bupropion and in the range of 20 to 50% as potent as bupropion in mouse models of depression.[1][2] Moreover, threohydrobupropion has been reported to weakly inhibit the reuptake of norepinephrine, dopamine, and serotonin with rat IC50Tooltip half-maximal inhibitory concentration or Ki values of 16 μM, 47 μM, and 67 μM, respectively.[4] These values can be compared to rat values with bupropion of 1,400 nM, 570 nM, and 19,000 nM, respectively.[4] Besides monoamine reuptake inhibition, threohydrobupropion has also been reported to inhibit α3β4 nicotinic acetylcholine receptors, with an IC50 value of 14 μM.[5] Threohydrobupropion circulates at higher concentrations than bupropion during bupropion therapy, similarly to hydroxybupropion but in contrast to erythrohydrobupropion—which circulates at similar concentrations as bupropion.[1][2]

The plasma protein binding of threohydrobupropion is 42%.[1] Threohydrobupropion is formed from bupropion via reduction of the ketone group by 11β-hydroxysteroid dehydrogenase-1 and aldo-keto reductases.[1] It can also be formed from bupropion by carbonyl reductases.[1][2] The compound is metabolized by the cytochrome P450 enzymes CYP2B6 and CYP2C19 into threo-4'-hydroxy-hydrobupropion and by various glucuronosyltransferase enzymes into glucuronide conjugates.[1] Its elimination half-life is approximately 37 hours.[1][2]

Dry mouth during bupropion therapy has been associated with threohydrobupropion concentrations.[1] Administration of threohydrobupropion in mice produces seizures at sufficiently high doses similarly to bupropion and other metabolites.[1] Threohydrobupropion is a CYP2D6 inhibitor and accounts for about 21% of CYP2D6 inhibition during bupropion therapy, with hydroxybupropion accounting for 65% and erythrohydrobupropion accounting for 9%.[1]

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. S2CID 163167323.
  2. ^ a b c d e f g Jefferson JW, Pradko JF, Muir KT (November 2005). "Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations". Clin Ther. 27 (11): 1685–95. doi:10.1016/j.clinthera.2005.11.011. PMID 16368442.
  3. ^ Masters AR, Gufford BT, Lu JB, Metzger IF, Jones DR, Desta Z (August 2016). "Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers". J Pharmacol Exp Ther. 358 (2): 230–8. doi:10.1124/jpet.116.232876. PMC 4959100. PMID 27255113.
  4. ^ a b Sánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cell Mol Neurobiol. 19 (4): 467–89. doi:10.1023/a:1006986824213. PMID 10379421. S2CID 19490821.
  5. ^ Bondarev ML, Bondareva TS, Young R, Glennon RA (August 2003). "Behavioral and biochemical investigations of bupropion metabolites". Eur J Pharmacol. 474 (1): 85–93. doi:10.1016/s0014-2999(03)02010-7. PMID 12909199.