Allopregnanolone, also known as brexanolone, is a medication and a naturally produced steroid that acts on the brain.[4][5] As a medication, it is sold under the brand name Zulresso[6] and used to treat postpartum depression.[5][7][8] It is used by injection into a vein over a 60-hour period under medical supervision.[5]

Allopregnanolone
Skeletal formula of allopregnanolone
Ball-and-stick model of the allopregnanolone molecule
Clinical data
Trade namesZulresso
Other namesBrexanolone; ALLO; Allo; ALLOP; AlloP; SAGE-547; SGE-102; 5α-Pregnan-3α-ol-20-one; 3α-Hydroxy-5α-pregnan-20-one; 3α,5α-Tetrahydroprogesterone; 3α,5α-THP
AHFS/Drugs.comMonograph
MedlinePlusa619037
License data
Routes of
administration
Intravenous infusion[1]
Drug classNeurosteroids; Antidepressants
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral: <5%[3]
Protein binding>99%[1][3]
MetabolismNon-CYP450 (keto-reduction via aldo-keto reductases (AKR), glucuronidation via glucuronosyltransferases (UGT), sulfation via sulfotransferases (SULT))[1][3]
Elimination half-life9 hours[1][3]
ExcretionFeces: 47%[1][3]
Urine: 42%[1][3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H34O2
Molar mass318.501 g·mol−1
3D model (JSmol)

Side effects of brexanolone may include sedation, sleepiness, dry mouth, hot flashes, and loss of consciousness.[1][5] It is a neurosteroid and acts as a positive allosteric modulator of the GABAA receptor, the major biological target of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).[1]

Brexanolone was approved for medical use in the United States in 2019, with commercial sales expected to begin in June 2019.[5] The long administration time, as well as the cost of US$34,000, have raised concerns about accessibility for many women.[9]

Medical usesEdit

Brexanolone is used to treat postpartum depression in women.[5]

Side effectsEdit

Side effects of brexanolone includs sedation (13–21%), dry mouth (3–11%), loss of consciousness (3–5%), and flushing (2–5%).[1][5][3] It can also produce euphoria to a degree similar to that of alprazolam (3–13% at infusion doses of 90–270 μg over a one hour period).[1]

Biological functionEdit

Allopregnanolone possesses a wide variety of effects, including, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[10] prosocial,[11] antiaggressive,[12] prosexual,[11] sedative, pro-sleep,[13] cognitive, memory-impairment, analgesic,[14] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[4] Fluctuations in the levels of allopregnanolone and the other neurosteroids seem to play an important role in the pathophysiology of mood, anxiety, premenstrual syndrome, catamenial epilepsy, and various other neuropsychiatric conditions.[15][16][17]

During pregnancy, allopregnanolone and pregnanolone are involved in sedation and anesthesia of the fetus.[18][19]

Mechanism of actionEdit

Molecular interactionsEdit

Allopregnanolone is an endogenous inhibitory pregnane neurosteroid.[4] It is made from progesterone, and is a positive allosteric modulator of the action of γ-aminobutyric acid (GABA) at GABAA receptor.[4] Allopregnanolone has effects similar to those of other positive allosteric modulators of the GABA action at GABAA receptor such as the benzodiazepines, including anxiolytic, sedative, and anticonvulsant activity.[4][20][21] Endogenously produced allopregnanolone exerts a neurophysiological role by fine-tuning of GABAA receptor and modulating the action of several positive allosteric modulators and agonists at GABAA receptor.[22]

Allopregnanolone acts as a highly potent positive allosteric modulator of the GABAA receptor.[4] While allopregnanolone, like other inhibitory neurosteroids such as THDOC, positively modulates all GABAA receptor isoforms, those isoforms containing δ subunits exhibit the greatest potentiation.[23] Allopregnanolone has also been found to act as a positive allosteric modulator of the GABAA-ρ receptor, though the implications of this action are unclear.[24][25] In addition to its actions on GABA receptors, allopregnanolone, like progesterone, is known to be a negative allosteric modulator of nACh receptors,[26] and also appears to act as a negative allosteric modulator of the 5-HT3 receptor.[27] Along with the other inhibitory neurosteroids, allopregnanolone appears to have little or no action at other ligand-gated ion channels, including the NMDA, AMPA, kainate, and glycine receptors.[28]

Unlike progesterone, allopregnanolone is inactive at the classical nuclear progesterone receptor (PR).[28] However, allopregnanolone can be intracellularly oxidized into 5α-dihydroprogesterone, which does act as an agonist of the PR, and for this reason, allopregnanolone can produce PR-mediated progestogenic effects.[29][30] In addition, allopregnanolone has recently been found to be an agonist of the newly discovered membrane progesterone receptors (mPRs), including mPRδ, mPRα, and mPRβ, with its activity at these receptors about a magnitude more potent than at the GABAA receptor.[31][32] The action of allopregnanolone at these receptors may be related, in part, to its neuroprotective and antigonadotropic properties.[31][33] Also like progesterone, recent evidence has shown that allopregnanolone is an activator of the pregnane X receptor.[28][34]

Similarly to many other GABAA receptor positive allosteric modulators, allopregnanolone has been found to act as an inhibitor of L-type voltage-gated calcium channels (L-VGCCs),[35] including α1 subtypes Cav1.2 and Cav1.3.[36] However, the threshold concentration of allopregnanolone to inhibit L-VGCCs was determined to be 3 μM (3,000 nM), which is far greater than the concentration of 5 nM that has been estimated to be naturally produced in the human brain.[36] Thus, inhibition of L-VGCCs is unlikely of any actual significance in the effects of endogenous allopregnanolone.[36] Also, allopregnanolone, along with several other neurosteroids, has been found to activate the G protein-coupled bile acid receptor (GPBAR1, or TGR5).[37] However, it is only able to do so at micromolar concentrations, which, similarly to the case of the L-VGCCs, are far greater than the low nanomolar concentrations of allopregnanolone estimated to be present in the brain.[37]

Biphasic actions at the GABAA receptorEdit

Increased levels of allopregnanolone can produce paradoxical effects, including negative mood, anxiety, irritability, and aggression.[38][39][40] This appears to be because allopregnanolone possesses biphasic, U-shaped actions at the GABAA receptor – moderate level increases (in the range of 1.5–2 nmol/L total allopregnanolone, which are approximately equivalent to luteal phase levels) inhibit the activity of the receptor, while lower and higher concentration increases stimulate it.[38][39] This seems to be a common effect of many GABAA receptor positive allosteric modulators.[15][40] In accordance, acute administration of low doses of micronized progesterone (which reliably elevates allopregnanolone levels) has been found to have negative effects on mood, while higher doses have a neutral effect.[41]

Antidepressant effectsEdit

The mechanism by which neurosteroid GABAA receptor PAMs like brexanolone have antidepressant effects is unknown.[42] Other GABAA receptor PAMs, such as benzodiazepines, are not known to have antidepressant effects.[42] Neurosteroid GABAA receptor PAMs are known to interact with GABAA receptors and sub-populations differently than benzodiazepines.[42] As examples, GABAA receptor-potentiating neurosteroids may preferentially target δ subunit-containing GABAA receptors, and enhance both tonic and phasic inhibition mediated by GABAA receptors.[42] It is also possible that neurosteroids like allopregnanolone may act on other targets, including membrane progesterone receptors, T-type voltage-gated calcium channels, and others, to mediate antidepressant effects.[42]

PharmacologyEdit

PharmacokineticsEdit

Brexanolone has low oral bioavailability of less than 5%, necessitating non-oral administration.[3] The volume of distribution of brexanolone is approximately 3 L/kg.[3] Its plasma protein binding is more than 99%.[1][3] Brexanolone is metabolized by keto-reduction mediated via aldo-keto reductases.[1][3] The compound is also conjugated by glucuronidation via glucuronosyltransferases and sulfation via sulfotransferases.[1] It is not metabolized importantly by the cytochrome P450 system.[1][3] The three main metabolites of brexanolone are inactive.[3] The elimination half-life of brexanolone is 9 hours.[1][3] Its total plasma clearance is 1 L/h/kg.[3] It is excreted 47% in feces and 42% in urine.[1][3] Less than 1% is excreted as unchanged brexanolone.[3]

ChemistryEdit

Allopregnanolone is a pregnane (C21) steroid and is also known as 5α-pregnan-3α-ol-20-one, 3α-hydroxy-5α-pregnan-20-one, or 3α,5α-tetrahydroprogesterone (3α,5α-THP). It is closely related structurally to 5-pregnenolone (pregn-5-en-3β-ol-20-dione), progesterone (pregn-4-ene-3,20-dione), the isomers of pregnanedione (5-dihydroprogesterone; 5-pregnane-3,20-dione), the isomers of 4-pregnenolone (3-dihydroprogesterone; pregn-4-en-3-ol-20-one), and the isomers of pregnanediol (5-pregnane-3,20-diol). In addition, allopregnanolone is one of four isomers of pregnanolone (3,5-tetrahydroprogesterone), with the other three isomers being pregnanolone (5β-pregnan-3α-ol-20-one), isopregnanolone (5α-pregnan-3β-ol-20-one), and epipregnanolone (5β-pregnan-3β-ol-20-one).

BiosynthesisEdit

The biosynthesis of allopregnanolone in the brain starts with the conversion of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid dehydrogenase converts this intermediate into allopregnanolone.[4] Allopregnanolone in the brain is produced by cortical and hippocampus pyramidal neurons and pyramidal-like neurons of the basolateral amygdala.[43]

DerivativesEdit

A variety of synthetic derivatives and analogues of allopregnanolone with similar activity and effects exist, including alfadolone (3α,21-dihydroxy-5α-pregnane-11,20-dione), alfaxolone (3α-hydroxy-5α-pregnane-11,20-dione), ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one), hydroxydione (21-hydroxy-5β-pregnane-3,20-dione), minaxolone (11α-(dimethylamino)-2β-ethoxy-3α-hydroxy-5α-pregnan-20-one), Org 20599 (21-chloro-3α-hydroxy-2β-morpholin-4-yl-5β-pregnan-20-one), Org 21465 (2β-(2,2-dimethyl-4-morpholinyl)-3α-hydroxy-11,20-dioxo-5α-pregnan-21-yl methanesulfonate), and renanolone (3α-hydroxy-5β-pregnan-11,20-dione).

The 21-hydroxylated derivative of this compound, tetrahydrodeoxycorticosterone (THDOC), is an endogenous inhibitory neurosteroid with similar properties to those of allopregnanolone, and the 3β-methyl analogue of allopregnanolone, ganaxolone, is under development to treat epilepsy and other conditions, including post-traumatic stress disorder (PTSD).[4]

HistoryEdit

In March 2019, brexanolone was approved in the United States for the treatment of postpartum depression (PPD) in adult women.[5] Brexanolone is the first drug approved by the U.S. Food and Drug Administration (FDA) specifically for PPD.[5]

The efficacy of brexanolone was shown in two clinical studies in participants who received a 60-hour continuous intravenous infusion of brexanolone or placebo and were then followed for four weeks.[5] The FDA approved allopregnanolone based on evidence from three clinical trials, conducted in the United States, (Trial 1/NCT02942004, Trial 3/NCT02614541, Trial 2/ NCT02942017) of 247 women with moderate or severe postpartum depression.[44]

The FDA granted the application for brexanolone priority review designation, breakthrough therapy designation, and granted approval of allopregnanolone to Sage Therapeutics, Inc.[5]

Society and cultureEdit

NamesEdit

Allopregnanolone is the name of the molecule commonly used in the literature when it is discussed as an endogenous neurosteroid. Brexanolone is both the INN and USAN in the context of its use as a medication.[45][46]

Zulresso is a brand name of the medication.

Legal statusEdit

In the United States, brexanolone is a Schedule IV controlled substance.[2]

In the United States, allopregnanolone is available only through a restricted program called the Zulresso REMS Program that requires the drug be administered by a health care provider in a certified health care facility. The REMS requires that patients be enrolled in the program prior to administration of the drug.[5]

DoseEdit

It is given continuously by intravenous infusion over a period of 60 hours (2.5 days).[1] The dosage of brexanolone is progressively adjusted over a range of 30 to 90 μg/kg/hour during this period.[1]

Because of the risk of serious harm due to the sudden loss of consciousness, patients must be monitored for excessive sedation and sudden loss of consciousness and have continuous pulse oximetry monitoring (monitors oxygen levels in the blood).[5] While receiving the infusion, people must be accompanied during interactions with their child(ren).[5] The need for these steps is addressed in a Boxed Warning in the drug’s prescribing information.[5] People should be counseled on the risks of allopregnanolone treatment and instructed that they must be monitored for these effects at a health care facility for the entire 60 hours of infusion.[5] People should not drive, operate machinery, or do other dangerous activities until feelings of sleepiness from the treatment have completely gone away.[5]

Available formsEdit

Brexanolone is an aqueous mixture of synthetic allopregnanolone and sulfobutyl ether β-cyclodextrin (betadex sulfobutyl ether sodium), a solubilizing agent.[1][3] It is provided at an allopregnanolone concentration of 100 mg/20 mL (5 mg/mL) in single-dose vials for use by intravenous infusion.[1] Each mL of brexanolone solution contains 5 mg allopregnanolone, 250 mg sulfobutyl ether β-cyclodextrin, 0.265 mg citric acid monohydrate, 2.57 mg sodium citrate dihydrate, and water for injection.[1] The solution is hypertonic and must be diluted to a target concentration of 1 mg/mL with sterile water and sodium chloride prior to administration.[1] Five infusion bags are generally required for the full infusion.[1] More than five infusion bags are necessary for patients weighing more than 90 kg (200 lbs).[1]

ResearchEdit

Brexanolone was under development as an intravenously administered medication for the treatment of major depressive disorder, super-refractory status epilepticus, and essential tremor, but development for these indications was discontinued.[47]

Exogenous progesterone, such as oral progesterone, elevates allopregnanolone levels in the body with good dose-to-serum level correlations.[48] Due to this, it has been suggested that oral progesterone could be described as a prodrug of sorts for allopregnanolone.[48] As a result, there has been some interest in using oral progesterone to treat catamenial epilepsy,[49] as well as other menstrual cycle-related and neurosteroid-associated conditions. In addition to oral progesterone, oral pregnenolone has also been found to act as a prodrug of allopregnanolone,[50][51][52] though also of pregnenolone sulfate.[53]

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