Threohydrobupropion

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 a racemic mixture of two stereoisomers, (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 K_i 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]