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Major metabolite of the antidepressant bupropion From Wikipedia, the free encyclopedia
(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]
-Hydroxybupropion.svg) | |
| 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 | |
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| CAS Number | |
| PubChem CID | |
| ChemSpider | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| Chemical and physical data | |
| Formula | C13H18ClNO2 |
| Molar mass | 255.74 g·mol−1 |
| 3D model (JSmol) | |
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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]
| Compound | Monoamine reuptake inhibition | nAChR inhibition | Ref | |||||
|---|---|---|---|---|---|---|---|---|
| DA | NE | 5-HT | α3β4 | α4β2 | α4β4 | α1β1 | ||
| Bupropion | 660–2,900 | 1,450–1,850 | >10,000–47,000 | 1,800 | 12,000 | 12,000–14,000 | 7,900 | [12][7][6] |
| (2R,3R)-Hydroxybupropion | >10,000 | 9,900 | >10,000 | 6,500 | 31,000 | 41,000 | 7,600 | [7][6] |
| (2S,3S)-Hydroxybupropion | 630 | 241 | >10,000 | 10,000–11,000 | 3,300 | 30,000 | 28,000 | [7][6] |
| Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site. | ||||||||
| Compound | DAT | NET | ||||||
|---|---|---|---|---|---|---|---|---|
| Bupropion | 550 ± 65 | 1900 ± 12 | ||||||
| (2RS,3RS)-Hydroxybupropion | >10000 | 1700 ± 830 | ||||||
| (2S,3S)-Hydroxybupropion | 790 ± 11 | 520 ± 35 | ||||||
| (2R,3R)-Hydroxybupropion | >10000 | >10000 | ||||||
| Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site. | ||||||||
Additional studies have characterized the affinities (Ki) 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]
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