(2''R'',3''R'')-Hydroxybupropion, or simply (''R'',''R'')-hydroxybupropion, is the major

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

of the

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

smoking cessation Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is Addiction, addictive and can cause Substance dependence, dependence. As a resu ...

, and

appetite suppressant An anorectic is a drug that reduces appetite, resulting in lower food consumption, leading to weight loss. These substances work by affecting the central nervous system or certain neurotransmitters to create a feeling of fullness or reduce the desi ...

medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

. It is the (2''R'',3''R'')-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

hydroxybupropion Hydroxybupropion (code name BW 306U), 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 ...

, which in humans occurs as a

mixture In chemistry, a mixture is a material made up of two or more different chemical substances which can be separated by physical method. It is an impure substance made up of 2 or more elements or compounds mechanically mixed together in any proporti ...

of (2''R'',3''R'')-hydroxybupropion and (2''S'',3''S'')-hydroxybupropion (radafaxine). Hydroxybupropion is formed from bupropion mainly by the

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

. Levels of (2''R'',3''R'')-hydroxybupropion are dramatically higher than those of bupropion and its other metabolites during bupropion therapy.

Exposure with bupropion

Bupropion is substantially converted into metabolites during

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism at a specific location in the body which leads to a reduction in the concentration of the active drug before it reaches the ...

with

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

and levels of its metabolites are much higher than those of bupropion itself. Exposure to (2''R'',3''R'')-hydroxybupropion is 29-fold higher than to (''R'')-bupropion and exposure to (2''S'',3''S'')-hydroxybupropion is 3.7-fold higher than to (''S'')-bupropion. Other metabolites that circulate at higher concentrations than those of bupropion include

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). Bupropion is a no ...

and to a lesser extent

erythrohydrobupropion Erythrohydrobupropion (developmental codes BW 287, BW 17U) is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a minor active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepine ...

. The

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of bupropion and its metabolites is

stereoselective In chemistry, stereoselectivity is the property of a chemical reaction in which a single reactant forms an unequal mixture of stereoisomers during a non- stereospecific creation of a new stereocenter or during a non-stereospecific transformation o ...

. During bupropion therapy, exposure to (''R'')-bupropion is 2- to 6-fold higher than to (''S'')-bupropion and exposure to (2''R'',3''R'')-hydroxybupropion is 20- to 65-fold higher than to (2''S'',3''S'')-hydroxybupropion. Hence, (2''R'',3''R'')-hydroxybupropion is a major metabolite of bupropion and (2''S'',3''S'')-hydroxybupropion is a minor metabolite. In contrast to humans, only low levels of hydroxybupropion or (2''R'',3''R'')-hydroxybupropion occur with bupropion in rats. This highlights substantial species differences in the

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific su ...

of bupropion between animals and humans. These differences in turn may account for differences in the

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

effects of bupropion between species.

Pharmacology

Pharmacodynamics

(2''R'',3''R'')-Hydroxybupropion is much less pharmacologically active as a

monoamine reuptake inhibitor A monoamine reuptake inhibitor (MRI) is a drug that acts as a reuptake inhibitor of one or more of the three major monoamine neurotransmitters serotonin, norepinephrine, and dopamine by blocking the action of one or more of the respective monoamin ...

than bupropion or (2''S'',3''S'')-hydroxybupropion. Conversely, its

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...

as a

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimuli. Some of them, like benzodiazepines or alcohol, function as psychoactive drugs. The site that a ...

nicotinic acetylcholine receptor Nicotinic acetylcholine receptors, or nAChRs, are Receptor (biochemistry), receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the c ...

s is variable but overall more similar to that of bupropion and (2''S'',3''S'')-hydroxybupropion. 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. In contrast to bupropion and (2''S'',3''S'')-hydroxybupropion, racemic hydroxybupropion, using rat proteins, has been found to act as a selective

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

(IC₅₀ = 1,700nM) with no apparent inhibition of dopamine reuptake (IC₅₀ > 10,000nM). Normally, activity with racemic mixtures is expected to be closer to that of the active enantiomer than to the inactive enantiomer. The reasons for the discrepancy in the case of racemic hydroxybupropion are unclear. In any case, it was suggested that (2''R'',3''R'')-hydroxybupropion might be acting as a negative allosteric modulator of the binding of (2''S'',3''S'')-hydroxybupropion to the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

. Bupropion and (2''S'',3''S'')-hydroxybupropion are substantially more potent than (2''R'',3''R'')-hydroxybupropion in various rodent behavioral tests, such as the

forced swim test ''Forced'' is a single-player and co-op action role-playing game developed by BetaDwarf, released in October 2013 for Windows, OS X and Linux through the Steam platform as well as Wii U. It is about gladiators fighting for their freedom in a fant ...

(an assay of antidepressant-like activity). However, sufficient doses of bupropion, (2''S'',3''S'')-hydroxybupropion, and (2''R'',3''R'')-hydroxybupropion all produce full

methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug use, recreational or Performance-enhancing substance, performance-enhancing drug and less commonly as a secon ...

-like effects in monkeys (1mg/kg, 3mg/kg, and 10mg/kg, respectively). Bupropion produces

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

-like effects in rodents and (2''S'',3''S'')-hydroxybupropion partially substitutes for nicotine. In contrast, (2''R'',3''R'')-hydroxybupropion does not substitute for nicotine and dose-dependently antagonizes the effects of nicotine by up to 50%. (2''R'',3''R'')-Hydroxybupropion is a strong

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2 ...

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

similarly to bupropion. (2''R'',3''R'')-Hydroxybupropion alone has been estimated to account for approximately 65% of the total ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' CYP2D6 inhibition of bupropion, whereas

accounted for 21% and

accounted for 9% (with 5% remaining or unaccounted for).

Pharmacokinetics

Hydroxybupropion, including both (2''R'',3''R'')-hydroxybupropion and (2''S'',3''S'')-hydroxybupropion, is mainly formed from bupropion by the

. However,

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some ...

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

, and

CYP2E1 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...

appear to play a minor role. CYP2B6 is highly polymorphic and is subject to high interindividual variability of approximately 100-fold. This may result in large interindividual differences in the metabolism of bupropion into hydroxybupropion and the effects of bupropion. However, clearance of bupropion is not affected in different CYP2B6 metabolizer phenotypes. This suggests that other enzymes compensate in the metabolism of bupropion in the context of reduced CYP2B6 function. The moderate CYP2B6

inducer In molecular biology, an inducer is a molecule that regulates gene expression. An inducer functions in two ways; namely: *By disabling repressors. The gene is expressed because an inducer binds to the repressor. The binding of the inducer to the r ...

rifampicin Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), ''Mycobacterium avium'' complex, leprosy, and Legionnaires' disease. It is almost always used tog ...

increased the clearance of (2''R'',3''R'')-hydroxybupropion and decreased its exposure and half-life by approximately 50%. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of (2''R'',3''R'')-hydroxybupropion is 19 to 26hours.

Chemistry

Hydroxybupropion has two

chiral center In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...

s. As a result, there are four possible

s of the

compound Compound may refer to: Architecture and built environments * Compound (enclosure), a cluster of buildings having a shared purpose, usually inside a fence or wall ** Compound (fortification), a version of the above fortified with defensive struc ...

. However, only (2''R'',3''R'')-hydroxybupropion and (2''S'',3''S'')-hydroxybupropion are formed in humans. (2''R'',3''S'')- and (2''S'',3''R'')-Hydroxybupropion do not occur in humans presumably due to

steric hindrance Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...

precluding their formation.

References

{{DEFAULTSORT:Hydroxybupropion, (2R,3R)- Antidepressants Cathinones 3-Chlorophenyl compounds CYP2D6 inhibitors Enantiopure drugs Human drug metabolites Morpholines Nicotinic antagonists Norepinephrine–dopamine reuptake inhibitors Smoking cessation Stimulants Tertiary alcohols