Quinagolide

Identification

Summary

Quinagolide is a dopamine D2 receptor agonist used for the treatment of hyperprolactinemia.

Generic Name

Quinagolide

DrugBank Accession Number

DB09097

Background

Quinagolide is a non-ergot-derived selective dopamine D2 receptor agonist used for the treatment of elevated levels of prolactin or hyperprolactinaemia. Hyperprolalctinaemia is associated with gonadal dysfunction, including infertility and reduced libido, as well as long-term complications such as osteoporosis ¹. Newer dopamine receptor agonists such as quinagolide and Cabergoline are shown to effectively inhibit prolactin secretion with improved efficacy over Bromocriptine. These drugs are effective in patients who are intolerant or resistant to Bromocriptine. Quinagolide exists as a racemate and its relevant clinical activity is mediated predominantly by the (-) enantiomer. It is typically present in the hydrochloride salt form and is marketed as oral tablets under the brand name Norprolac contained as a racemate. Quinagolide is currently available in several countries including Canada, but not approved for treatment in the United States.

Type

Small Molecule

Groups

Approved, Investigational

Structure

Similar Structures

Weight: Average: 395.56
Monoisotopic: 395.224263109
Chemical Formula: C₂₀H₃₃N₃O₃S

Synonyms

(+-)-N,N-Diethyl-N'-((3R*,4aR*,10aS*)-1,2,3,4,4a,5,10,10a-octahydro-6-hydroxy-1-propylbenzo(g)quinolin-3-yl)sulfamide
Quinagolida
Quinagolide
Quinagolidum

Pharmacology

Indication

Indicated for the treatment of hyperprolactinemia (idiopathic or originating from a prolactin-secreting pituitary microadenoma or macroadenoma).

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Quinagolide achieves long-lasting reduction in prolactin levels in a dose-proportional effect via selectively targeting D2 receptors as an agonist. It potently suppresses both basal and stimulated serum prolactin levels by exerting a strong inhibitory effect on the secretion of the anterior pituitary hormone prolactin.

Mechanism of action

Prolactin secretion from the lactotroph cells present in the anterior pituiatry gland is under tonic inhibitory control mediated by dopaminergic signalling via D2 receptors ⁵. Quinagolide selectively binds to D2 receptors expressed on the surface of lactotroph cells with high affinity which results in reduced adenylyl cyclase activity, reduced intracellular cyclic adenosine monophosphate and inhibited prolactin secretion. It also binds to D1 receptors but with low affinity and little clinical relevance ¹.

Target	Actions	Organism
UDopamine D2 receptor	agonist	Humans
UD(1) dopamine receptor	agonist	Humans

Absorption

The absorption of quinagolide is rapid and extensive with 95% of the dose absorbed after oral ingestion, however the absolute bioavailability is low (4 %) due to pre-systemic metabolism. The time to reach peak plasma concentration is 30-60 minutes. Prolactin-lowering effect of quinagolide at recommended therapeutic doses occurs within 2 hours after ingestion reaches a maximum within 4 to 6 hours and is maintained for at least 24 hours ⁷.

Volume of distribution

Approximate volume of distribution is 100L following a single oral admininstration. The parent drug and metabolites is predicted to be extensively distributed in the extravascular compartment with primary target organs being the liver, kidneys, salivary glands and pituitary ^Label.

Protein binding

Plasma protein binding is reported to be non-specific with an approximate ratio of 90%.

Metabolism

Quinagolide undergoes extensive first pass metabolism with sulfate and glucuronide conjugates being the major circulating metabolites. N-desethyl analogue is a biologically active metabolite while sulfate or glucuronide conjugates and N,N-didesethyl analogue are inactive metabolites.

Route of elimination

More than 95% of total dose is excreted as metabolites and the excretion via urine and feces is approximately equal. Renal elimination accounts for 50% of total elimination, where sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues can be detected in the urine. Unconjugated forms of sulfate or glucuronide conjugates, N-desethyl and N,N-didesethyl analogues are excreted into feces, and fecal elimination accounts for 40% of the total elimination of the drug.

Half-life

The terminal half-life for parent drug is 11.5 hours following single dose and 17 hours at steady state.

Clearance

Not Available

Adverse Effects

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Toxicity

Most commonly observed adverse effects are nausea, vomiting, headache, dizziness and fatigue that usually appear in the beginning of initial therapy. Less frequent side effects (1 to 10%) include anorexia, abdominal pain, constipation or diarrhoea, insomnia, oedema, flushing, nasal congestion and hypotension. Orthostatic hypotension may result in faintness or syncope ^Label. Quinagolide demonstrates carcinogenic potential in animal studies but with no known relevance in humans. It is not demonstrated to be embryotoxic or teratogenic, but it is associated with reduced pregnancy rates ⁶. Oral LD50 values in mouse, rat and rabbit are 300 mg/kg, 980 mg/kg and 3200 mg/kg, respectively ^MSDS.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Acetophenazine	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Acetophenazine.
Alimemazine	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Alimemazine.
Amisulpride	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Amisulpride.
Amoxapine	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Amoxapine.
Apomorphine	The risk or severity of adverse effects can be decreased when Apomorphine is combined with Quinagolide.
Aripiprazole	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Aripiprazole.
Aripiprazole lauroxil	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Aripiprazole lauroxil.
Asenapine	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Asenapine.
Benperidol	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Benperidol.
Brexpiprazole	The therapeutic efficacy of Quinagolide can be decreased when used in combination with Brexpiprazole.

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Food Interactions

Avoid excessive or chronic alcohol consumption. Alcohol may increase the risk of dizziness, thereby reducing the tolerability of quinagolide.
Take with a light meal or snack. Food reduces gastric irritation.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Quinagolide hydrochloride	33474X943Y	94424-50-7	DVLKVIJLALMCBQ-VENMBWNLSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Norprolac	Tablet	0.15 mg	Oral	Ferring Pharmaceuticals	2004-12-29	2021-06-02
Norprolac	Tablet	0.025 mg	Oral	Ferring Pharmaceuticals	2004-12-29	2021-06-02
Norprolac	Tablet	0.075 mg	Oral	Ferring Pharmaceuticals	2004-12-29	2020-12-09
Norprolac	Tablet	0.05 mg	Oral	Ferring Pharmaceuticals	2004-12-29	2021-06-02

Chemical Identifiers

UNII: 80Q9QWN15M
CAS number: 87056-78-8
InChI Key: GDFGTRDCCWFXTG-ZIFCJYIRSA-N
InChI: InChI=1S/C20H33N3O3S/c1-4-10-22-14-17(21-27(25,26)23(5-2)6-3)11-16-12-18-15(13-19(16)22)8-7-9-20(18)24/h7-9,16-17,19,21,24H,4-6,10-14H2,1-3H3/t16-,17+,19-/m1/s1
IUPAC Name: (3S,4aS,10aR)-3-[(diethylsulfamoyl)amino]-1-propyl-1H,2H,3H,4H,4aH,5H,10H,10aH-benzo[g]quinolin-6-ol
SMILES: [H][C@]12C[C@@H](CN(CCC)[C@]1([H])CC1=CC=CC(O)=C1C2)NS(=O)(=O)N(CC)CC

References

General References

Barlier A, Jaquet P: Quinagolide--a valuable treatment option for hyperprolactinaemia. Eur J Endocrinol. 2006 Feb;154(2):187-95. [Article]
Di Sarno A, Landi ML, Marzullo P, Di Somma C, Pivonello R, Cerbone G, Lombardi G, Colao A: The effect of quinagolide and cabergoline, two selective dopamine receptor type 2 agonists, in the treatment of prolactinomas. Clin Endocrinol (Oxf). 2000 Jul;53(1):53-60. [Article]
Schultz PN, Ginsberg L, McCutcheon IE, Samaan N, Leavens M, Gagel RF: Quinagolide in the management of prolactinoma. Pituitary. 2000 Dec;3(4):239-49. [Article]
Busso C, Fernandez-Sanchez M, Garcia-Velasco JA, Landeras J, Ballesteros A, Munoz E, Gonzalez S, Simon C, Arce JC, Pellicer A: The non-ergot derived dopamine agonist quinagolide in prevention of early ovarian hyperstimulation syndrome in IVF patients: a randomized, double-blind, placebo-controlled trial. Hum Reprod. 2010 Apr;25(4):995-1004. doi: 10.1093/humrep/deq005. Epub 2010 Feb 6. [Article]
32. (2012). In Rang and Dale's Pharmacology (7th ed., pp. 397-398). Edinburgh: Elsevier/Churchill Livingstone. [ISBN:978-0-7020-3471-8]
DRUG NAME: Quinagolide - BC Cancer Agency [Link]
NORPROLAC® (quinagolide) Product information [Link]

External Links

PubChem Compound: 3086401
PubChem Substance: 310265024
ChemSpider: 2343034
BindingDB: 50225362
RxNav: 76887
ChEBI: 135627
ChEMBL: CHEMBL290962
ZINC: ZINC000003778441
Wikipedia: Quinagolide

FDA label

Download (301 KB)

MSDS

Download (78.9 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Completed	Prevention	Ovarian Hyper Stimulation Syndrome (OHSS)	1
2	Completed	Treatment	Endometriosis	1
2	Completed	Treatment	Ovarian Hyper Stimulation Syndrome (OHSS)	1
2	Recruiting	Treatment	Endometriosis related pain	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	0.025 mg
Tablet	Oral	0.05 mg
Tablet	Oral	0.15 mg
Tablet	Oral
Tablet	Oral	0.075 mg

Prices

Not Available

Patents

Not Available

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	231-237	FDA Label/Product monograph
water solubility	Sparingly soluble in water (0.2%)	FDA Label/Product monograph

Predicted Properties

Property	Value	Source
Water Solubility	0.154 mg/mL	ALOGPS
logP	2.56	ALOGPS
logP	2.5	ChemAxon
logS	-3.4	ALOGPS
pKa (Strongest Acidic)	10.2	ChemAxon
pKa (Strongest Basic)	8.22	ChemAxon
Physiological Charge	1	ChemAxon
Hydrogen Acceptor Count	5	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	72.88 Å²	ChemAxon
Rotatable Bond Count	5	ChemAxon
Refractivity	109.66 m³·mol^-1	ChemAxon
Polarizability	44.11 Å³	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Dopamine D2 receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: Potassium channel regulator activity
Specific Function: Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase.
Gene Name: DRD2
Uniprot ID: P14416
Uniprot Name: D(2) dopamine receptor
Molecular Weight: 50618.91 Da

Details2. D(1) dopamine receptor (Protein Group)

Kind: Protein group
Organism: Humans
Pharmacological action: Unknown
Actions: Agonist

General Function: G-protein coupled amine receptor activity
Specific Function: Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase.

Components:

Name	UniProt ID
D(1A) dopamine receptor	P21728
D(1B) dopamine receptor	P21918

References

Barlier A, Jaquet P: Quinagolide--a valuable treatment option for hyperprolactinaemia. Eur J Endocrinol. 2006 Feb;154(2):187-95. [Article]

Drug created on September 16, 2015 18:24 / Updated on October 15, 2021 19:56

Quinagolide

Identification

Structure for Quinagolide (DB09097)

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Targets

Components:

References