Threohydrobupropion

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
IUPAC name
  • 2-(tert-butylamino)-1-(3-chlorophenyl)propan-1-ol
CAS Number
PubChem CID
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.216.731
Chemical and physical data
FormulaC13H20ClNO
Molar mass241.76 g·mol−1
3D model (JSmol)
SMILES
  • CC(C(C1=CC(=CC=C1)Cl)O)NC(C)(C)C
InChI
  • 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. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 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. 1 2 3 4 5 6 7 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. 1 2 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.


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