(2R,3R)-Hydroxybupropion

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(2R,3R)-Hydroxybupropion
(2R,3R)-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
  • (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethylmorpholin-2-ol
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)
  • C[C@@H]1[C@](OCC(N1)(C)C)(C2=CC(=CC=C2)Cl)O
  • 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]

Contents

Exposure with bupropion

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]

Pharmacology

Pharmacodynamics

(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]

Bupropion and hydroxybupropion functional activities (IC50) at human biological targets [9] [10] [11]
CompoundMonoamine reuptake inhibitionnAChR inhibitionRef
DANE5-HTα3β4α4β2α4β4α1β1
Bupropion 660–2,9001,450–1,850>10,000–47,0001,80012,00012,000–14,0007,900 [12] [7] [6]
(2R,3R)-Hydroxybupropion>10,0009,900>10,0006,50031,00041,0007,600 [7] [6]
(2S,3S)-Hydroxybupropion 630241>10,00010,000–11,0003,30030,00028,000 [7] [6]
Notes: Values are in nanomolar (nM) units. The smaller the value, the more avidly the compound affects the site.
Bupropion and hydroxybupropion inhibition (IC50, nM) of rat monoamine transporters [6]
CompoundDATNET
Bupropion 550 ± 651900 ± 12
(2RS,3RS)-Hydroxybupropion >100001700 ± 830
(2S,3S)-Hydroxybupropion 790 ± 11520 ± 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]

Pharmacokinetics

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]

Chemistry

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]

Related Research Articles

<span class="mw-page-title-main">Bupropion</span> Medication mainly used for depression and smoking cessation

Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cases of "incomplete response" to the first-line selective serotonin reuptake inhibitor (SSRI) antidepressant. Bupropion has several features that distinguish it from other antidepressants: it does not usually cause sexual dysfunction, it is not associated with weight gain and sleepiness, and it is more effective than SSRIs at improving symptoms of hypersomnia and fatigue. Bupropion, particularly the immediate release formulation, carries a higher risk of seizure than many other antidepressants, hence caution is recommended in patients with a history of seizure disorder. The medication is taken by mouth.

A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

<span class="mw-page-title-main">Catechin</span> Type of natural phenol as a plant secondary metabolite

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<span class="mw-page-title-main">Trimipramine</span> Antidepressant

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<span class="mw-page-title-main">Radafaxine</span> Chemical compound

Radafaxine (developmental code GW-353,162; also known as (2S,3S)-hydroxybupropion or (S,S)-hydroxybupropion) is a norepinephrine–dopamine reuptake inhibitor (NDRI) which was under development by GlaxoSmithKline in the 2000s for a variety of different indications but was never marketed. These uses included treatment of restless legs syndrome, major depressive disorder, bipolar disorder, neuropathic pain, fibromyalgia, and obesity. Regulatory filing was planned for 2007, but development was discontinued in 2006 due to "poor test results".

<span class="mw-page-title-main">CYP2B6</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

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<span class="mw-page-title-main">Serotonin–dopamine reuptake inhibitor</span> Class of drug

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<span class="mw-page-title-main">Hydroxybupropion</span> Group of stereoisomers

Hydroxybupropion, or 6-hydroxybupropion, is the major active metabolite of the antidepressant and smoking cessation drug bupropion. It is formed from bupropion by the liver enzyme CYP2B6 during first-pass metabolism. With oral bupropion treatment, hydroxybupropion is present in plasma at area under the curve concentrations that are as many as 16 to 20 times greater than those of bupropion itself, demonstrating extensive conversion of bupropion into hydroxybupropion in humans. As such, hydroxybupropion is likely to play a very important role in the effects of oral bupropion, which could accurately be thought of as functioning largely as a prodrug to hydroxybupropion.

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<span class="mw-page-title-main">Threohydrobupropion</span> Type of substituted amphetamine derivative

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References

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  15. ↑ Banks ML, Smith DA, Blough BE (April 2016). "Methamphetamine-like discriminative stimulus effects of bupropion and its two hydroxy metabolites in male rhesus monkeys". Behav Pharmacol. 27 (2-3 Spec Issue): 196–203. doi:10.1097/FBP.0000000000000224. PMC   4779668 . PMID   26886209.
  16. 1 2 3 Niemegeers P, Dumont GJ, Patteet L, Neels H, Sabbe BG (September 2013). "Bupropion for the treatment of seasonal affective disorder". Expert Opin Drug Metab Toxicol. 9 (9): 1229–1240. doi:10.1517/17425255.2013.804062. PMID   23705752. As hydroxybupropion has two chiral centers, there are four possible enantiomers. However, only (R,R)-hydroxybupropion and (S,S)-hydroxybupropion are found in human plasma [62].
  17. 1 2 3 Eap CB, Gründer G, Baumann P, Ansermot N, Conca A, Corruble E, Crettol S, Dahl ML, de Leon J, Greiner C, Howes O, Kim E, Lanzenberger R, Meyer JH, Moessner R, Mulder H, Müller DJ, Reis M, Riederer P, Ruhe HG, Spigset O, Spina E, Stegman B, Steimer W, Stingl J, Suzen S, Uchida H, Unterecker S, Vandenberghe F, Hiemke C (October 2021). "Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants". World J Biol Psychiatry. 22 (8): 561–628. doi:10.1080/15622975.2021.1878427. hdl: 11250/2981927 . PMID   33977870. Bupropion is chiral and CYP2B6 stereoselective metabolism is observed with (S)-bupropion being metabolised at more than three times the rate of (R)-bupropion (Coles and Kharasch 2008). Because hydroxybupropion has two chiral centres, four enantiomers should be observed: however, only (R,R)-hydroxybupropion and (S,S)- hydroxybupropion are found (Coles and Kharasch 2008).
  18. ↑ Batra S, Bhushan R (May 2016). "Resolution of enantiomers of bupropion and its metabolites by liquid chromatography". Biomed Chromatogr. 30 (5): 670–682. doi:10.1002/bmc.3572. PMID   26230937. S,S)- and (R,R)-hydroxybupropion have been found in plasma in humans, presumably owing to steric hindrance precluding formation of (R,S)- and (S,R)-hydroxybupropion.
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