(2R,3R)-Hydroxybupropion

Clinical data
Other names	(R,R)-Hydroxybupropion
Pharmacokinetic data
Metabolism	Glucuronidation[1][2]
Metabolites	Hydroxybupropion glucuronide[1][2]
Elimination half-life	19–26 hours[1][2]
Identifiers
IUPAC name (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol
CAS Number	192374-15-5
PubChem CID	9943908
ChemSpider	8119520
ChEMBL	ChEMBL1172929
CompTox Dashboard (EPA)	DTXSID40433176
Chemical and physical data
Formula	C13H18ClNO2
Molar mass	255.74 g·mol−1
3D model (JSmol)	Interactive image
SMILES C[C@@H]1[C@](OCC(N1)(C)C)(C2=CC(=CC=C2)Cl)O
InChI 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]

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]

(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]

Additional studies have characterized the affinities (K_i) 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]

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]

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]