Hydroxybupropion (code name BW 306U), or 6-hydroxybupropion, is the major

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

of the

antidepressant Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...

and

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

drug bupropion. It is formed from bupropion by the

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enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

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. Funct ...

during

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...

. With oral bupropion treatment, hydroxybupropion is present in

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concentrations that are as many as 16–20 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 A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

to hydroxybupropion. Other metabolites of bupropion besides hydroxybupropion 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 ...

and

erythrohydrobupropion Erythrohydrobupropion (developmental code names 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 ...

Pharmacology

Pharmacodynamics

Compared to bupropion, hydroxybupropion is similar in its

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as a

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( IC₅₀ = 1.7 μM), but is substantially weaker as a

dopamine reuptake inhibitor 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 dopa ...

(IC₅₀ = >10 μM). Like bupropion, hydroxybupropion is also a

non-competitive antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...

of nACh receptors, such as α₄β₂ and α₃β₄, but is even more potent in comparison.

Pharmacokinetics

Bupropion is extensively and rapidly absorbed in the gastrointestinal tract but experiences extensive first pass metabolism rendering its systemic bioavailability limited. Exact bioavailability has yet to be determined given an intravenous form does not exist. Absorption is suggested to be between 80-90%. Its distribution half-life is between 3–4 hours and exhibits moderate human plasma protein binding (between 82–88%) with the parent compound and hydroxybupropion displaying the highest affinity. Bupropion is a racemic mixture and is metabolized hepatically primarily via oxidative cleavage of its side chains by CYP2B6. Hydroxybupropion is the most potent of the metabolites. It is formed via the "''hydroxylation of the tert-butyl group''" by CYP2B6 and is excreted renally. C_max vales of hydroxybupropion are 4–7 times that of bupropion, while the exposure to hydroxybupropion is "10 fold" that of bupropion. Hydroxybupropion's elimination half-life is roughly 20 hours, give or take 5 hours and will reach steady state concentrations within 8 days.

Chemistry

Hydroxybupropion is a

racemic mixture In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

of (''R'',''R'')-hydroxybupropion and (''S'',''S'')-hydroxybupropion.

Research

Although there are patents proposing uses and formulations of this compound, hydroxybuproprion is not currently marketed as a drug in and of itself and is only available for use in non-clinical research. Hydroxybupropion is not a scheduled drug or a controlled substance. One can access GLP (Good Lab Practice) documents detailing assays/techniques to further research and isolate this drug. Otherwise, there is little regulatory data available for hydroxybupropion at this time. Moreover, there is little information to suggest hydroxybupropion has an abuse potential. However, it has been studied as a possible therapeutic for alcohol and nicotine use as a codrug. There are few clinical trials or toxicology studies assessing hydroxybupropion alone at this time. There are clinical studies which assess hydroxybupropion in conjunction with bupropion suggesting hydroxybupropion to be the primary form of the compound responsible for its clinical efficacy. Also, transdermal delivery of bupropion and hydroxybupropion has been assessed finding bupropion to be the superior candidate given its elevated diffusion rate through skin samples. There are few toxicology studies assessing hydroxybupropion alone at this time. However, there are some studies which assess this compound in conjunction with others or its parent compound.

References