Absorption, Distribution and Excretion
Apomorphine has a plasma Tmax of 10-20 minutes and a cerebrospinal fluid Tmax. The Cmax and AUC of apomorphine vary significantly between patients, with 5- to 10-fold differences being reported.
Data regarding apomorphine's route of elimination is not readily available. A study in rats has shown apomorphine is predominantly eliminated in the urine.
The apparent volume of distribution of subcutaneous apomorphine is 123-404L with an average of 218L. The apparent volume of distribution of sublingual apomorphine is 3630L.
The clearance of a 15mg sublingual dose of apomorphine is 1440L/h, while the clearance of an intravenous dose is 223L/h.
The plasma-to-whole blood apomorphine concentration ratio is equal to one. Mean (range) apparent volume of distribution was 218 L (123 - 404 L). Maximum concentrations in cerebrospinal fluid (CSF) are less than 10% of maximum plasma concentrations and occur 10 to 20 minutes later.
Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed (time to peak concentration ranges from 10 to 60 minutes) following subcutaneous administration into the abdominal wall. After subcutaneous administration, apomorphine appears to have bioavailability equal to that of an intravenous administration. Apomorphine exhibits linear pharmacokinetics over a dose range of 2 to 8 mg following a single subcutaneous injection of apomorphine into the abdominal wall in patients with idiopathic Parkinson's disease. /Apomorphine hydrochloride/
In the treatment of patients with Parkinson's disease, apomorphine has an established place as a back-up therapy if other antiparkinsonian drugs, such as levodopa and oral dopamine agonists, have not controlled the existing response fluctuations. Apomorphine is a synthetic derivative of morphine, with a totally distinct pharmacological profile. It is a very lipophilic compound which is easily (auto)oxidized. This (auto)oxidation is the main metabolic route besides glucuronidation and sulfation, which are both responsible for about 10% of the metabolic transformation. Apomorphine quickly passes the nasal and intestinal mucosa as well as the blood-brain barrier (depending on the administration route). Many routes of administration have been explored, but subcutaneous, sublingual, nasal and rectal administration are used in clinical practice. The volume of distribution varies between 1 and 2 times bodyweight. The elimination half-life is very short (30 to 90 min) depending on the type of parenteral administration. Apomorphine is a high clearance drug (3 to 5 L/kg/hr) and is mainly excreted and metabolised by the liver. Only 3 to 4% is excreted unchanged in the urine. The clinical effect of apomorphine can be linked directly to its concentration in the cerebrospinal fluid. Consequently, a 2-compartment model can be used to predict the clinical effects of apomorphine. The pharmacokinetic-pharmacodynamic data reflect the clinical observations of steep dose-effect curves if apomorphine is used in patients with random 'on-off' fluctuations. These dose-effect curves are less steep in stable or 'wearing-off' (end-of-dose deterioration) patients. Intravenous infusions of apomorphine in combination with timed motor assessments can be used clinically to characterize the therapeutic window of a particular patient if dyskinesia persists after single injections of apomorphine. If more population data become available, the population pharmacokinetics-pharmacodynamics of apomorphine could be helpful in predicting the clinical effects of apomorphine in the several subgroups of patients with Parkinson's disease.

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Metabolism / Metabolites
Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuronidated by various UGTs, or sulfated by SULTs 1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is eliminated as a sulfate conjugate, though the structure of these sulfate conjugates are not readily available. The remainder of an apomorphine dose is eliminated as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneous apomorphine is recovered as the unchanged parent drug.
Routes of apomorphine metabolism in humans are not known. Potential metabolic routes include sulfation, N-demethylation, glucuronidation, and oxidation.1 Apomorphine undergoes rapid auto-oxidation in vitro. Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine. In vitro studies have suggested that apomorphine may be metabolized by COMT. Data from in vivo studies indicate that apomorphine is not metabolized by COMT.
Hepatic
Half Life: 40 minutes (range 30 - 60 minutes)

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Biological Half-Life
The terminal elimination half life of a 15mg sublingual dose of apomorphine is 1.7h, while the terminal elimination half life of an intravenous dose is 50 minutes.
The mean terminal elimination half-life is about 40 minutes (range about 30 to 60 minutes).

Hepatotoxicity
Apomorphine has not been reported to cause serum aminotransferase elevations or clinically apparent acute liver injury, but its use has been limited and is typically given in low doses for a limited period of time. Thus, if apomorphine causes liver injury it must be rare.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of apomorphine during breastfeeding. If apomorphine is required by the mother, it is not a reason to discontinue breastfeeding. However, apomorphine inhibits prolactin release in animals and might interfere with establishment of lactation. An alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Apomorphine is expected to be 99.9% bound to human serum albumin, as no unbound apomorphine is detected.

[1]. Subcutaneous apomorphine in the treatment of Parkinson's disease. J Neurol Neurosurg Psychiatry. 1990 Feb;53(2):96-101.

[2]. Apomorphine for Parkinson's Disease: Efficacy and Safety of Current and New Formulations. CNS Drugs. 2019 Sep;33(9):905-918.

Apomorphine is an aporphine alkaloid. It has a role as an alpha-adrenergic drug, a serotonergic drug, an antidyskinesia agent, a dopamine agonist, an antiparkinson drug and an emetic. It derives from a hydride of an aporphine.
Apomorphine is a non-ergoline dopamine D2 agonist indicated to treat hypomobility associated with Parkinson's. It was first synthesized in 1845 and first used in Parkinson's disease in 1884. Apomorphine has also been investigated as an emetic, a sedative, a treatment for alcoholism, and a treatment of other movement disorders. Apomorphine was granted FDA approval on 20 April 2004.
Apomorphine is a Dopaminergic Agonist. The mechanism of action of apomorphine is as a Dopamine Agonist.
Apomorphine is a subcutaneously administered dopamine receptor agonist used predominantly in the therapy of hypomobility of advanced Parkinson disease. The use of apomorphine has been limited, but it has not been associated with serum enzyme elevations during treatment nor has it been implicated in cases of acute liver injury.
Apomorphine Hydrochloride is the hydrochloride salt form of apomorphine, a derivative of morphine and non-ergoline dopamine agonist with high selectivity for dopamine D2, D3, D4 and D5 receptors. Apomorphine hydrochloride acts by stimulating dopamine receptors in the nigrostriatal system, hypothalamus, limbic system, pituitary gland, and blood vessels. This enhances motor function, suppresses prolactin release, and causes vasodilation and behavioral effects. Apomorphine hydrochloride is used in the treatment of Parkinson's disease and erectile dysfunction. In addition, apomorphine hydrochloride acts on the chemoreceptor trigger zone and is used as a central emetic in the treatment of drug overdose.
A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use. [PubChem]
A derivative of morphine that is a dopamine D2 agonist. It is a powerful emetic and has been used for that effect in acute poisoning. It has also been used in the diagnosis and treatment of parkinsonism, but its adverse effects limit its use.
See also: Apomorphine Hydrochloride (has salt form); Apomorphine Diacetate (has salt form).

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Drug Indication
Apomorphine is indicated to treat acute, intermittent treatment of hypomobility, off episodes associated with advanced Parkinson's disease.
FDA Label
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Uprima to be effective, sexual stimulation is required.
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Taluvian to be effective, sexual stimulation is required.
Treatment of men with erectile dysfunction, which is the inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. In order for Ixense to be effective, sexual stimulation is required.

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Mechanism of Action
Apomorphine is a non-ergoline dopamine agonist with high binding affinity to dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate-putamen, a region of the brain responsible for locomotor control, may be responsible for apomorphine's action. However, the means by which the cellular effects of apomorphine treat hypomobility of Parkinson's remain unknown.
The exact mechanism of action of apomorphine hydrochloride in the treatment of Parkinson's disease has not been fully elucidated but may involve stimulation of postsynaptic dopamine D2 receptors within the caudate-putamen in the brain. Apomorphine has been shown to improve motor function in an animal model of Parkinson's disease. In particular, apomorphine attenuates the motor deficits associated with neurotoxin (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ([MPTP])-induced lesions in the ascending nigrostriatal dopaminergic pathway in primates.
Apomorphine hydrochloride is a nonergot-derivative dopamine receptor agonist that is structurally and pharmacologically related to dopamine. In in vitro studies, apomorphine hydrochloride demonstrated a higher affinity for the dopamine D4 receptor than for dopamine D2, D3, or D5 receptors. Apomorphine hydrochloride binds with moderate affinity to alpha-adrenergic (alpha1D, alpha2B, alpha2C) receptors but has little or no affinity for dopamine D1 receptors, serotonergic (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C) receptors, beta1- or beta2-adrenergic receptors, or histamine H1 receptors. /Apomorphine hydrochloride/

C17H18NO2+

268.33032

267.126

58-00-4

58-00-4;314-19-2 (HCl);41372-20-7 (HCl hydrate);41035-30-7 (S-isomer HCl); 39478-62-1 (S-isomer);

6005

Green to dark green solid powder

1.299 g/cm3

473.4ºC at 760 mmHg

195ºC (decomposes)

268.8ºC

2.787

2

3

0

20

374

1

CN1CCC2=C3[C@H]1CC4=C(C3=CC=C2)C(=C(C=C4)O)O

VMWNQDUVQKEIOC-CYBMUJFWSA-N

InChI=1S/C17H17NO2/c1-18-8-7-10-3-2-4-12-15(10)13(18)9-11-5-6-14(19)17(20)16(11)12/h2-6,13,19-20H,7-9H2,1H3/t13-/m1/s1

(6aR)-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-10,11-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)