Absorption, Distribution and Excretion
The time to peak plasma concentration (Tmax) of apomorphine is 10-20 minutes, and the time to peak cerebrospinal fluid concentration (Tmax) is also 10-20 minutes. The peak plasma concentration (Cmax) and area under the curve (AUC) of apomorphine vary significantly among different patients, reportedly differing by 5-10 times. Data on the elimination pathway of apomorphine are unclear. A rat study showed that apomorphine is primarily excreted in the urine. The apparent volume of distribution of subcutaneously administered apomorphine is 123-404 L, with an average of 218 L. The apparent volume of distribution of sublingually administered apomorphine is 3630 L. The clearance of 15 mg sublingually administered apomorphine is 1440 L/h, while the clearance of intravenously administered apomorphine is 223 L/h. The plasma to whole blood concentration ratio of apomorphine is 1. The mean (range) apparent volume of distribution is 218 L (123–404 L). The maximum concentration in cerebrospinal fluid (CSF) is less than 10% of the maximum plasma concentration and occurs 10–20 minutes later than the maximum plasma concentration. Apomorphine hydrochloride is a lipophilic compound that is rapidly absorbed after subcutaneous injection into the abdominal wall (peak absorption time 10–60 minutes). The bioavailability of apomorphine after subcutaneous injection appears to be comparable to that after intravenous injection. In patients with idiopathic Parkinson's disease, the pharmacokinetics of apomorphine are linear in the 2–8 mg dose range after a single subcutaneous injection into the abdominal wall. Apomorphine hydrochloride can be used as an alternative therapy in the treatment of Parkinson's disease if other anti-Parkinson's drugs (e.g., levodopa and oral dopamine agonists) fail to control existing efficacy fluctuations. Apomorphine is a synthetic derivative of morphine and has entirely different pharmacological properties. It is a highly lipophilic compound, readily undergoing (auto)oxidation. Besides glucuronidation and sulfation (accounting for approximately 10% of metabolic conversion), (auto)oxidation is its primary metabolic pathway. Apomorphine rapidly crosses the nasal and intestinal mucosa and the blood-brain barrier (depending on the route of administration). Various routes of administration have been explored, but subcutaneous, sublingual, nasal, and rectal administration are commonly used in clinical practice. Its volume of distribution is 1 to 2 times its body weight. Depending on the parenteral administration route, apomorphine has a short elimination half-life (30–90 minutes). Apomorphine is a high-clearance drug (3–5 liters/kg/hour), primarily excreted and metabolized by the liver. Only 3%–4% is excreted unchanged in the urine. The clinical efficacy of apomorphine is directly related to its concentration in the cerebrospinal fluid. Therefore, a two-compartment model can be used to predict the clinical efficacy of apomorphine. Pharmacokinetic-pharmacodynamic data reflect clinical observations, showing steep dose-response curves in patients with randomized "on-off" fluctuations of apomorphine. These curves are flatter in patients with stable disease or "regression" (decreased efficacy at the end of administration). If motor dysfunction persists after a single apomorphine injection, a combination of intravenous apomorphine infusion and timed motor assessment can be used to clinically determine the treatment window for specific patients. With more population data available, population pharmacokinetic-pharmacodynamic data for apomorphine will help predict its clinical efficacy in different subgroups of Parkinson's disease patients.

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Metabolism/Metabolites
Apomorphine is N-demethylated by CYP2B6, 2C8, 3A4, and 3A5. It can be glucuroninated by various UGTs or sulfated by SULT1A1, 1A2, 1A3, 1E1, and 1B1. Approximately 60% of sublingual apomorphine is excreted as sulfate conjugates, but the structures of these sulfate conjugates are not fully understood. The remaining dose of apomorphine is excreted as apomorphine glucuronide and norapomorphine glucuronide. Only 0.3% of subcutaneously injected apomorphine is recovered in its virgin form. The metabolic pathways of apomorphine in humans are not fully understood. Possible pathways include sulfation, N-demethylation, glucuronidation, and oxidation. In vitro studies have shown that apomorphine undergoes rapid auto-oxidation. Cytochrome P-450 (CYP) enzymes play a minor role in the metabolism of apomorphine. In vitro studies suggest that apomorphine may be metabolized via catecholamine-O-methyltransferase (COMT). In vivo data indicate that apomorphine is not metabolized by COMT.
Liver
Half-life: 40 minutes (range 30-60 minutes)

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Biological Half-life
The terminal elimination half-life of 15 mg apomorphine administered sublingually is 1.7 hours, while the terminal elimination half-life of intravenous injection is 50 minutes.
The average terminal elimination half-life is approximately 40 minutes (range approximately 30 to 60 minutes).

Hepatotoxicity
There are no reports of apomorphine causing elevated serum transaminases or clinically symptomatic acute liver injury, but its use is restricted and usually administered at low doses for short periods. Therefore, if apomorphine does cause liver injury, this is certainly very rare. Probability score: E (Unlikely to cause clinically symptomatic liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information regarding the use of apomorphine during lactation. If the mother needs to use apomorphine, breastfeeding should not be discontinued. However, apomorphine inhibits the release of prolactin in animals and may interfere with the establishment of lactation. Especially in breastfeeding newborns or premature infants, alternative medications may need to be considered. ◉ Effects on Breastfed Infants No relevant published information was found as of the revision date. ◉ Effects on Lactation and Breast Milk No relevant published information was found as of the revision date.

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Protein Binding
The expected binding rate of apomorphine to human serum albumin is 99.9%, as no free apomorphine was 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 apophene alkaloid. It possesses a variety of pharmacological effects, including alpha-adrenergic, serotonergic, anti-movement disorder, dopamine agonist, anti-Parkinson's disease drug, and emetic. It is derived from the hydrogenated form of apomorphine. Apomorphine is a non-ergot dopamine D2 receptor agonist used to treat movement disorders associated with Parkinson's disease. It was first synthesized in 1845 and first used to treat Parkinson's disease in 1884. Apomorphine has also been investigated for its use as an emetic, sedative, and treatment of alcoholism and other movement disorders. Apomorphine was approved by the U.S. Food and Drug Administration (FDA) on April 20, 2004. Apomorphine is a dopamine agonist. Its mechanism of action is as a dopamine agonist. Apomorphine is a subcutaneously injected dopamine receptor agonist primarily used to treat the decline in mobility in patients with advanced Parkinson's disease. Although the use of apomorphine is limited, it has not been found to cause elevated serum enzymes during treatment, nor has it been found to be associated with cases of acute liver injury. Apomorphine hydrochloride is the hydrochloride form of apomorphine, a derivative of morphine, and a non-ergot dopamine agonist with high selectivity for dopamine D2, D3, D4, and D5 receptors. Apomorphine hydrochloride acts by stimulating dopamine receptors in the substantia nigra-striatal system, hypothalamus, limbic system, pituitary gland, and blood vessels. This can enhance motor function, inhibit prolactin release, and cause vasodilation and behavioral changes. Apomorphine hydrochloride is used to treat Parkinson's disease and erectile dysfunction. In addition, apomorphine hydrochloride acts on chemoreceptor trigger zones and can be used as a centrally acting emetic for drug overdose. Morphine is a derivative of morphine and belongs to the dopamine D2 receptor agonist class. It is a potent emetic and has been used to treat acute poisoning. It has also been used for the diagnosis and treatment of Parkinson's disease, but its adverse effects limit its application. [PubChem]
Morphine is a derivative of morphine and belongs to the dopamine D2 receptor agonist class. It is a potent emetic and has been used to treat acute poisoning. It has also been used for the diagnosis and treatment of Parkinson's disease, but its adverse effects limit its application.
See also: Apomorphine hydrochloride (salt form); Apomorphine diacetate (salt form).

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Drug Indications
Apomorphine is indicated for the treatment of acute, intermittent hypoactivity and “off-peak” symptoms associated with advanced Parkinson's disease.
FDA Label
For the treatment of erectile dysfunction in men, i.e., the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Uprima requires sexual stimulation to be effective.
For the treatment of erectile dysfunction in men, i.e., the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Taluvian requires sexual stimulation to be effective.
Used to treat erectile dysfunction in men, i.e., the inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Sexual stimulation is required for Ixense to be effective.

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Mechanism of Action
Apomorphine is a non-ergot dopamine agonist with high affinity for dopamine D2, D3, and D5 receptors. Stimulation of D2 receptors in the caudate nucleus-putamen (a region of the brain responsible for motor control) is likely the reason apomorphine works. However, the cellular effector mechanism of apomorphine in treating motor disorders in Parkinson's disease is unclear.
The exact mechanism of action of apomorphine hydrochloride in treating Parkinson's disease is not fully elucidated, but it may involve stimulation of postsynaptic dopamine D2 receptors in the caudate nucleus-putamen of the brain. Apomorphine has been shown to improve motor function in animal models of Parkinson's disease. Specifically, apomorphine can alleviate motor dysfunction caused by damage to the ascending dopaminergic pathway in the substantia nigra-striatum of primates induced by neurotoxins (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Apomorphine hydrochloride is a non-ergot dopamine receptor agonist with dopamine-related structural and pharmacological properties. In vitro studies have shown that apomorphine hydrochloride has a higher affinity for dopamine D4 receptors than for dopamine D2, D3, or D5 receptors. Apomorphine hydrochloride has moderate affinity for α-adrenergic receptors (α1D, α2B, α2C), but very low or no affinity for dopamine D1 receptors and serotonergic receptors (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C). It also contains β1- or β2-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.)