ロピニロール

3.06

log Kow = 2.70

2.3

133

3.53e-01 g/L

243-250 °C

243 - 250 °C

163.27 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；159.22 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；161.49 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

162.5 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

163.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]；H412 (100%): Harmful to aquatic life with long lasting effects [Hazardous to the aquatic environment, long-term hazard]

P264, P270, P273, P301+P317, P330, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ropinirole hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ropinirole hydrochloride/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Ropinirole hydrochloride/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Ropinirole hydrochloride/

Store at controlled room temperature 20 deg - 25 °C (68 deg - 77 °F). Protect from light and moisture. Close container tightly after each use.

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. /Ropinirole hydrochloride/

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Ropinirole hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product. /Ropinirole hydrochloride/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection. /Ropinirole hydrochloride/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Ropinirole hydrochloride/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Ropinirole hydrochloride/

Skin protection: Handle with gloves. /Ropinirole hydrochloride/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Ropinirole hydrochloride/

Body Protection: Complete suit protecting against chemicals, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Ropinirole hydrochloride/

Eye/face protection: Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Ropinirole hydrochloride/

Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of Requip.

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy (HRT)) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of Requip.

No information is available on the potential for interaction between Requip and alcohol. As with other centrally active medications, patients should be cautioned against taking Requip with alcohol.

The effect of Requip (2 mg t.i.d.) on the pharmacokinetics of digoxin (0.125-0.25 mg o.d.) was studied in male and female patients with Parkinson's disease (n=10, mean age 72 years). Coadministration at steady state with Requip resulted in a 10% decrease in digoxin AUC although mean trough digoxin plasma concentrations were unaltered. However, the effect of higher recommended doses of Requip on the pharmacokinetics of digoxin is not known.

For more Interactions (Complete) data for ROPINIROLE (12 total), please visit the HSDB record page.

Ropinirole has been reported to cause serum aminotransferase or alkaline phosphatase elevations in a small proportion of patients, but these abnormalities are usually mild, asymptomatic and self-limiting even without dose adjustment. Ropinirole has been implicated in a small number of cases of acute liver injury, but the clinical characteristics and typical pattern of enzyme elevations has not been characterized. In one case report, the time to onset was 2 months and the pattern of liver enzyme elevations was mixed and associated with marked jaundice. Immunoallergic and autoimmune features were not present. The injury resolved within 2 months of stopping. Thus, ropinirole can cause acute, clinically apparent liver injury with jaundice, but it is rare.；Likelihood score: D (possible, rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that ropinirole is expected to have low mobility in soil(SRC). The estimated pKa of the tertiary amine of ropinirole is 10.17(4), indicating that this compound will exist almost in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Ropinirole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that ropinirole is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of the tertiary amine of 10.17(4) indicates ropinirole will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 28(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ropinirole, which has an estimated vapor pressure of 6.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ropinirole may be removed from the air by wet and dry deposition(SRC). Ropinirol contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Rare cases of hypersensitivity reactions, falling asleep during activities of daily living, somnolence (especially if concomitantly using CNS depressants), hallucinations, compulsive behaviors, augmentation, early morning rebound RLS, fibrotic complications, and retinal degeneration are also reported in clinical trials and postmarketing experience.；Peripheral edema: Peripheral edema has been reported in up to one-third of the patients on the extended-release form.；Anterocollis: The definition of this condition is the head positioned in flexion, resembling a "drooping head," a rare side effect reported in a patient taking ropinirole. Discontinuation of the medication progressively reversed the symptoms within 4 months.；Pisa syndrome: Cases of ropinirole-induced Pisa syndrome, referred to as "pleurothotonus," have been recorded. The condition is characterized by an abnormal lateral flexion of the trunk to the right or left. This condition occurred after a year on the medication and resolved 3 months after cessation of treatment. However, some reports maintain that Pisa syndrome is irreversible despite discontinuing this medication.；Reversible dyskinesias: Another movement disorder observed with ropinirole is severe reversible dyskinesias, which is very rare. This dose-dependent choreoform dyskinesia occurred in ropinirole monotherapy up to a dose of 15 mg daily but was also observed at a dose of 6 mg daily.；Dermal eruptions: Similar to other D2 agonists, ropinirole rarely caused fixed dermal eruptions. This adverse effect is thought to be due to the inactivation of T cells.；Dopamine-agonist withdrawal syndromes: Withdrawal-emergent hyperpyrexia and confusion are reported in patients where ropinirole treatment is abruptly stopped or the dose is rapidly tapered down. This condition resembles neuroleptic malignant syndrome without specific etiology. Withdrawal symptoms include insomnia, anxiety, apathy, depression, sweating, fatigue, and pain, which do not respond to treatment with levodopa. Recommendations include informing patients about the potential for withdrawal symptoms and monitoring symptoms during taper down and after treatment cessation.；Impulse control disorders: Case reports of increased sexual drive, gambling, and binge eating have been reported. The mechanism of action is thought to be the stimulation of dopamine D3 receptors by dopamine agonists. Patients have reported an inability to control their urges. Patients may not convey problems to clinicians due to embarrassment. In severe cases, clinicians should consider decreasing the dose of ropinirole; severe cases may require cessation of therapy. It acts as a dopamine agonist, which can trigger manic symptoms in susceptible patients.；Drug-Drug Interactions；CYP1A2 enzyme is induced by omeprazole and smoking and can decrease the plasma concentration of ropinirole. CYP1A2 is inhibited by fluoroquinolones (eg, ciprofloxacin and norfloxacin), fluvoxamine, and mexiletine. The administration of these drugs may increase the plasma level of this drug.；Hormone replacement therapy (HRT, high dose estrogens) reduces the clearance of ropinirole; dose adjustment may be required when starting or stopping HRT.；Dopamine antagonists phenothiazines, thioxanthenes, butyrophenones, and metoclopramide can reduce the efficacy of ropinirole. Concurrent administration of ropinirole and metoclopramide should be avoided.；As with most dopamine agonists, ropinirole's most frequently reported adverse effects include nausea, vomiting, dyspepsia, abdominal pain, hallucinations, drowsiness, dizziness, leg edema, viral infection, syncope, orthostatic hypotension, and asthenic condition (ie, weakness, fatigue, and malaise).

IDENTIFICATION AND USE: Ropinirole hydrochloride, a dipropylaminoethyl indolone derivative, is a nonergot-derivative dopamine receptor agonist. It is used for the symptomatic management of idiopathic parkinsonian syndrome. It is also used for the symptomatic management of moderate-to-severe primary restless legs syndrome (RLS).HUMAN EXPOSURE AND TOXICITY: The largest overdose reported with ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ropinirole, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and RLS. In some cases, although not all, these urges were reported to have

Ropinirole can cause death when taken with alcohol, and persons who excessively consume alcohol should not use the drug. A lethal level up to 6 times the therapeutic dose correlates with death.；Patients with liver insufficiency require close monitoring; a case report of liver toxicity exists. The medication is metabolized primarily in the liver, and the toxicity may be due to an immune reaction or a possible toxic metabolite.；Signs and Symptoms of Overdose；Of these patients who used doses exceeding 24 mg per day, commonly reported adverse reactions were related to its dopaminergic activity, ie, nausea, dizziness, hyperhidrosis, visual hallucinations, claustrophobia, palpitations, chorea, asthenia, and nightmares. Additional symptoms reported in overdose patients included vomiting, agitation, chest pain, increased coughing, fatigue, orthostatic hypotension, syncope, dyskinesia, somnolence, and a confusional state. A recent study describes shock and arrhythmias as the probable reason for mortality associated with ropinirole overdose.；Management of Overdose；There have been reports of patients who intentionally or accidentally took more than the maximum recommended daily dose of ropinirole in clinical trials. General supportive measures are recommended, and vitals should be maintained when necessary. In clinical trials, the most significant overdose reported with ropinirole was 62 mg daily for 7 days (total dose 435 mg).

Ropinirole binds the dopamine receptors D₃ and D₂. Although the precise mechanism of action of ropinirole as a treatment for Parkinson's disease is unknown, it is believed to be related to its ability to stimulate these receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that ropinirole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum.

Symptoms of overdose include agitation, chest pain, confusion, drowsiness, facial muscle movements, grogginess, increased jerkiness of movement, symptoms of low blood pressure (dizziness, light-headedness)upon standing, nausea, and vomiting.

The Koc of ropinirole is estimated as 1700(SRC), using a log Kow of 2.70(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that ropinirole is expected to have low mobility in soil. The estimated pKa of the tertiary amine of ropinirole is 10.17(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/HUMAN EXPOSURE STUDIES/ Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2-receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone-placebo, and those of a single dose of domperidone followed by ropinirole-placebo. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. Pretreatment with 20 mg domperidone 1 hr before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. Ropinirole did not alter supine or standing catecholamine concentrations. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 hr earlier.

/HUMAN EXPOSURE STUDIES/ Pramipexole and ropinirole are ... dopamine agonists, both of which have proven efficacy in the treatment of Parkinson's disease. There is, however, uncertainty regarding differences in the adverse event profiles associated with each drug. ... We systematically reviewed the medical literature to identify randomised controlled trials of pramipexole and ropinirole used in the management of Parkinson's disease. Computerised databases (including Medline, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts) were used to identify pertinent articles for inclusion in this study. Trials that compared the dopamine agonists to either levodopa or placebo were included. Adverse events with these drugs included dizziness, nausea, hypotension, hallucinations, and somnolence. We made two separate analyses. In the first analysis, we estimated the pooled relative risk (RR) of adverse events with either pramipexole or ropinirole as compared with levodopa. In the second analysis, the pooled RRs of adverse events with pramipexole and ropinirole were compared with placebo. We used the random-effects model of DerSimonian and Laird to estimate the RRs and their corresponding 95% CIs. We tested for study heterogeneity using Q statistics. RESULTS: There was no significant difference in the risk of dizziness, nausea, or hypotension with either drug individually or in combination when compared with levodopa. The risk of hypotension was approximately four times higher with ropinirole than pramipexole when each drug was individually compared with placebo (6.46 [95% CI 1.47-28.28] for ropinirole, and 1.65 [0.88-3.08] for pramipexole). The pooled RR (for pramipexole and ropinirole combined) of hallucinations was 1.92 (95% CI 1.08-3.43) when compared with levodopa. Relative to placebo, pramipexole had a significantly higher risk of hallucinations than ropinirole (pramipexole 5.2 (95% CI 1.97-13.72) vs ropinirole 2.75 (95% CI 0.55-13.73)). There was

/SIGNS AND SYMPTOMS/ Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Requip or after starting or increasing the dose of Requip. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

/SIGNS AND SYMPTOMS/ Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spendmoney, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Requip, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and restless legs syndrome (RLS). In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued.

For more Human Toxicity Excerpts (Complete) data for ROPINIROLE (18 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ropinirole hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ropinirole hydrochloride/

N04BC04

N - Nervous system；N04 - Anti-parkinson drugs；N04B - Dopaminergic agents；N04BC - Dopamine agonists；N04BC04 - Ropinirole

QN - Nervous system；QN04 - Anti-parkinson drugs；QN04B - Dopaminergic agents；QN04BC - Dopamine agonists；QN04BC04 - Ropinirole

QV - Various；QV03 - All other therapeutic products；QV03A - All other therapeutic products；QV03AB - Antidotes；QV03AB96 - Ropinirole

**Effects on Parkinson's and restless leg syndrome** This drug promotes the relief or improvement of symptoms of Parkinson's or restless leg syndrome by stimulatory actions on dopamine receptors, which regulate movement. **Effects on blood pressure** Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired abilities in regulating blood pressure with resulting orthostatic hypotension, especially with patients undergoing dose escalation. In some patients in clinical studies, blood pressure changes were associated with orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest accompanied by syncope. The mechanism of orthostatic hypotension caused by ropinirole is assumed to be due to a D2-mediated blunting of noradrenergic response to a standing position, followed by a decrease in peripheral vascular resistance. Nausea is also a frequent symptom which accompanies orthostatic signs and symptoms. **Effects on prolactin** At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers. Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg. **Effects on QT interval** Ropinirole had no dose- or exposure-related effect on average QT intervals in healthy male and female volunteers at doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures reached either due to drug interactions, hepatic dysfunction, or at higher doses has not been adequately evaluated.

Ropinirole is a non-ergoline dopamine agonist. Ropinirole has the highest affinity at the D3 receptors, which are concentrated in the limbic areas of the brain and may be responsible for some of the neuropsychiatric effects. The exact mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, however, it is believed to be related to its ability to selectively stimulate dopamine D2 receptors within the caudate-putamen system in the brain. This system affects body movement. Negligible affinity is seen for ropinirole at α2 adrenoreceptors in the periphery and 5HT-1 receptor. Ropinirole has no affinity at the D1-like receptors, benzodiazepine or GABA receptors. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, however, it is believed to be related to its ability to stimulate dopamine receptors.

The present study determined its affinity and agonist efficacy at recombinant human (h) dopamine hD2, hD3 and hD4 and serotonin (5-HT) h5-HT1A, h5-HT1B and h5-HT1D receptors. Roxindole exhibited high affinity at hD3 as well as at hD2 (short isoform) and hD4 (4-repeat isoform) receptors (pKi values 8.93, 8.55 and 8.23, respectively). Further, it displayed high affinity at hS-HT1A receptors (pKi = 9.42) but modest affinity at 5-HT1B and 5-HT1D receptors (pKi values 6.00 and 7.05, respectively). In [35S]GTPgammaS binding experiments, roxindole was >20-fold more potent in stimulating [35S]GTPgammaS binding at hD3 than at hD2 or hD4 receptors (pEC50 = 9.23 vs. 7.88 and 7.69). However, whereas roxindole exhibited partial agonist activity at hD3 and hD4 sites (Emax = 30.0% and 35.1%, respectively, relative to dopamine = 100%), it only weakly activated hD2 receptors (Emax = 10.5%). Roxindole potently blocked dopamine-stimulated [35S]GTPgammaS binding at hD2 receptors (pkappaB = 9.05). In comparison, the dopamine receptor agonist, (-)quinpirole, acted as a partial agonist at hD3 and hD4 sites (Emax = 67.4% and 66.3%, respectively) but surpassed the efficacy of dopamine at hD2 receptors (Emax = 132%). At h5-HT1A receptors, roxindole behaved as a high affinity (pKi = 9.42) partial agonist (Emax = 59.6%, relative to 5-HT = 100%), whereas (-)quinpirole had negligible activity. The selective 5-HT1A antagonist, WAY 100,635, blocked roxindole (100 nM)-stimulated [35S]GTPgammaS binding at h5-HT1A receptors in a concentration-dependent manner (pkappaB = 9.28). Roxindole only weakly stimulated [35S]GTPgammaS binding at 5-HT1B and 5-HT1D receptors (Emax = 27.1% and 13.7%). The present data suggest that roxindole activates mainly D3 vs. D2 or D4 receptors and 5-HT1A vs. 5-HT1B or 5-HT1D receptors. Activation of D3 and/or 5-HT1A receptors may thus contribute to its potential antidepressant properties.

The aim of the present study was to characterize functional responses to ropinirole, its major metabolites in man (SKF-104557 (4-[2-(propylamino)ethyl]-2-(3H) indolone), SKF-97930 (4-carboxy-2-(3H) indolone)) and other dopamine receptor agonists at human dopamine D2(long) (hD2), D3 (hD3) and D4.4 (hD4) receptors separately expressed in Chinese hamster ovary cells using microphysiometry. 2. All the receptor agonists tested (ropinirole, SKF-104557, SKF-97930, bromocriptine, lisuride, pergolide, pramipexole, talipexole, dopamine) increased extracellular acidification rate in Chinese hamster ovary clones expressing the human D2, D3 or D4 receptor. The pEC50s of ropinirole at hD2, hD3 and hD4 receptors were 7.4, 8.4 and 6.8, respectively. Ropinirole is therefore at least 10 fold selective for the human dopamine D3 receptor over the other D2 receptor family members. 3. At the hD2 and hD3 dopamine receptors all the compounds tested were full agonists as compared to quinpirole. Talipexole and the ropinirole metabolite, SKF-104557, were partial agonists at the hD4 receptor. 4. Bromocriptine and lisuride had a slow onset of agonist action which precluded determination of EC50s. 5. The rank order of agonist potencies was dissimilar to the rank order of radioligand binding affinities at each of the dopamine receptor subtypes. Functional selectivities of the dopamine receptor agonists, as measured in the microphysiometer, were less than radioligand binding selectivities. 6. The results show that ropinirole is a full agonist at human D2, D3 and D4 dopamine receptors. SKF-104557 the major human metabolite of ropinirole, had similar radioligand binding affinities to, but lower functional potencies than, the parent compound.

Ropinirole, which is a non-ergot dopamine agonist derivative, exerts therapeutic benefits in Parkinson's disease (PD). Based on recent studies implicating dopamine receptors 2 and 3 (D2R and D3R) as possible targets of ropinirole, we over-expressed these dopamine receptor genes in the dopamine-denervated striatum of rodents to reveal whether their over-expression modulated ropinirole activity. Adult Sprague-Dawley rats initially received unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. At 1 month after surgery, successfully lesioned animals (3 or less forelimb akinesia score, and 8 or more apomorphine-induced rotations/min over 1 hr) were randomly assigned to intrastriatal injection (ipsilateral to the lesion) of blank lentiviral vector, D2R, D3R or both genes. At about 5 months post-lesion, ropinirole (0.2 mg/kg, i.p.) was administered daily for 9 consecutive days. The subtherapeutic dose of ropinirole improved the use of previously akinetic forelimb and produced robust circling behavior in lesioned animals with striatal over-expression of both D2R and D3R compared to lesioned animals that received blank vector. In contrast, the subtherapeutic dose of ropinirole generated only modest motor effects in lesioned animals with sole over-expression of D2R or D3R. Western immunoblot and autoradiographic assays showed enhanced D2R and D3R protein levels coupled with normalized D2R and D3R binding in the ventral striatum of lesioned animals with lentiviral over-expression of both D2R and D3R relative to vehicle-treated lesioned animals. Immunohistochemical analyses showed that D2R and D3R GFP fluorescent cells colocalized with enkephalin and substance P immunoreactive medium spiny neurons. These data support the use of the subtherapeutic dose of ropinirole in a chronic model of PD.

Ropinirole hydrochloride, a dipropylaminoethyl indolone derivative, is a nonergot-derivative dopamine receptor agonist. In in vitro binding studies, ropinirole demonstrated high binding specificity for and intrinsic activity at dopamine D2 receptors compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide), having a higher affinity for the D3 subtype than for the D2 or D4 subtypes. Ropinirole binds with moderate affinity to opiate receptors but has little or no affinity for alpha1-, alpha2-, or beta-adrenergic; dopamine D1; benzodiazepine; gamma-aminobutyric acid (GABA); serotonin type 1 (5-hydroxytryptamine (5-HT1)); serotonin type 2 (5-HT2); or muscarinic receptors.

Approximately 6 hours,.

The terminal elimination half-life is approximately 6 hr (range 2-27 hr) ... .

The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. ... Terminal phase elimination half-lives for the compound were relatively short (0.5 and 1.3 hr in rat and monkey respectively), although there was evidence of a second elimination phase in the monkey with an elimination half-life of approximately 5-11 hr. ...

Ropinirole is heavily metabolized by the liver. The most important metabolic pathways are N­ despropylation and hydroxylation to form the _N-despropyl_ metabolite and _hydroxy_ metabolites, both of which are inactive. The _N-despropyl_ metabolite is then converted to _carbamyl glucuronide_, carboxylic acid, and _N-despropyl hydroxy_ metabolites. Following this process, the _hydroxy_ metabolite of ropinirole is glucuronidated at a rapid rate. _In vitro_ studies show that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2,.

Ropinirole is extensively metabolized by the liver. The N-despropyl metabolite is the major metabolite circulating in the plasma. Based on AUC data, the plasma levels of the metabolite were consistently higher than those of the parent drug suggesting a nonsaturable conversion of ropinirole to the N-despropyl metabolite. The affinity of the N-despropyl metabolite for human cloned D2 receptors is lower than the affinity of ropinirole. In addition the metabolite does not cross the blood-brain barrier; thus, it is unlikely to contribute to the therapeutic effects of ropinirole. The plasma concentrations of the hydroxylated metabolite are low and account for about 1-5% of the ropinirole concentrations. Although the hydroxylated metabolite was more active than ropinirole in in vitro D2 receptor binding studies, at therapeutic doses it is not expected to contribute to the activity of ropinirole.

The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. ... In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. ...

The dopamine receptor agonist ropinirole (SKF-101468) is used to treat Parkinson's disease. Ropinirole is metabolized by two routes to a series of different metabolites although the predominant pathway is species-dependent. It is unknown whether any of the metabolites contribute to its antiparkinsonian activity and whether D3 or D2 receptor agonist activity plays a preferential role. Therefore ropinirole and its primary metabolites, SKF-104557, SKF-97930 and SKF-96990, and the rat metabolite, SKF-89124 were tested in the 6-hydroxydopamine lesion model of Parkinson's disease. SKF-89124 and SKF-96990 were also assayed in radioligand binding and microphysiometer functional assays at cloned human dopamine D2 and D3. Ropinirole and SKF-89124 were equipotent in-vivo, and produced dose-related increases in circling at 0.05-0.8 mg kg(-1), s.c. (ropinirole) and 0.05-0.75 mg kg(-1), s.c. (SKF-89124). Neither SKF-96990 or SKF-97930, at doses up to 15 mg kg(-1), increased the circling rate. Some circling was observed with 15 mg kg(-1) SKF-104557 but the response was less than half that produced by ropinirole (0.8 mgkg(-1)). SKF-104557 was 150-fold less potent than ropinirole. SKF-89124 possessed-30-fold higher affinity for D3 over D2 receptors in radioligand binding studies, but was not selective in the functional microphysiometer assay. SKF-96990 was 10-fold selective for D3 over D2 receptors in the radioligand binding assay. Ropinirole and SKF-104557 are 20-fold selective for D3 over D2 receptors in radioligand binding assays whereas in microphysiometry, selectivity is 10-fold. SKF-97930 is inactive in radioligand binding and microphysiometer assays. Primary metabolites of ropinirole did not contribute significantly to its activity in this model of Parkinson's disease. The lack of dopamine D3/D2 receptor selectivity for ropinirole rules out the possibility of attributing the degree of either D2 or D3 receptor activity to the behavioural efficacy of ropinirole.

The in vitro metabolism of ropinirole was investigated with the aim of identifying the cytochrome P450 enzymes responsible for its biotransformation. The pathways of metabolism after incubation of ropinirole with human liver microsomes were N-despropylation and hydroxylation. Enzyme kinetics demonstrated the involvement of at least two enzymes contributing to each pathway. A high affinity component with a K(M) of 5-87 uM and a low affinity component with a K(M) of approximately two orders of magnitude greater were evident. The high affinity component could be abolished by pre-incubation of the microsomes with furafylline. Additionally, incubation of ropinirole with microsomes derived from CYP1A2 transfected cells readily produced the N-despropyl and hydroxy metabolites. Some inhibition of ropinirole metabolism was also observed with ketoconazole, indicating a minor contribution by CYP3A. Multivariate correlation data were consistent with the involvement of the cytochrome P450 enzymes 1A2 and 3A in the metabolism of ropinirole. Thus, it could be concluded that the major P450 enzyme responsible for ropinirole metabolism at lower (clinically relevant) concentrations is CYP1A2 with a contribution from CYP3A, particularly at higher concentrations.

Ropinirole has known human metabolites that include 4-(2-(Propylamino)ethyl)indolin-2-one and 4-[2-(Dipropylamino)ethyl]-7-hydroxy-1,3-dihydro-2h-indol-2-one.

030PYR8953

ROPINIROLE

Mechanisms of Action [MoA] - Dopamine Agonists

Established Pharmacologic Class [EPC] - Nonergot Dopamine Agonist

Ropinirole is a Nonergot Dopamine Agonist. The mechanism of action of ropinirole is as a Dopamine Agonist.

ROPINIROLE

Agents used in the treatment of Parkinson's disease. The most commonly used drugs act on the dopaminergic system in the striatum and basal ganglia or are centrally acting muscarinic antagonists.

Drugs that bind to and activate dopamine receptors.

Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours,. Absolute bioavailability was 45% to 55%, suggesting approximately 50% hepatic first-pass effect. The bioavailability of ropinirole prolonged release compared to the immediate release tablets is about 100%. Ingestion of food does not affect the absorption of ropinirole, although its Tmax was increased by 2.5 hours and its Cmax was reduced by approximately 25% when the drug is taken with a high-fat meal.

The majority of the absorbed dose is cleared by the liver. In clinical trials, more than 88% of a radiolabeled dose was recovered in urine. Less than 10% of the administered dose is excreted as unchanged drug in urine. _N-despropyl ropinirole_ is the major metabolite found in the urine (40%), followed by the _carboxylic acid_ metabolite (10%), and the _glucuronide_ of the hydroxy metabolite (10%).

Ropinirole is found to be widely distributed throughout the body, with an apparent volume of distribution of **7.5 L/kg**.

The clearance of ropinirole after oral administration is 47 L/h.

The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. In all species, nearly all of the p.o. administered dose (94%) was rapidly absorbed from the gastrointestinal tract following administration of (14)C-ropinirole hydrochloride. In rat and monkey, the compound distributed rapidly beyond total body water and was shown to cross the blood-brain barrier. Blood clearance of the compound was high, approximately equal to one-half the hepatic blood flow in the monkey and similar to the hepatic blood flow in rat. Terminal phase elimination half-lives for the compound were relatively short (0.5 and 1.3 hr in rat and monkey respectively), although there was evidence of a second elimination phase in the monkey with an elimination half-life of approximately 5-11 hr. Plasma concentrations of ropinirole after the intravenous dose were not determined in the mouse and were below the lower limit of quantification in man (0.08 ng/mL) at the doses used in the studies described in this paper. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. In all species, the major route of excretion of ropinirole-related material after oral or intravenous administration of the compound was renal (60-90% of dose).

Ropinirole is a selective non-ergoline dopamine D2 receptor agonist indicated for use in treating Parkinson's disease. When taken as oral tablets, ropinirole is rapidly and almost completely absorbed, and it is extensively distributed from the vascular compartment. The bioavailability is approximately 50%. Ropinirole shows low plasma protein binding. The drug is inactivated by metabolism in the liver, and none of the major circulating metabolites have pharmacological activity. The principal metabolic enzyme is the cytochrome P450 (CYP) isoenzyme CYP1A2. Ropinirole shows approximately linear pharmacokinetics when given as single or repeated doses, and is eliminated with a half-life of approximately 6 hours. Population pharmacokinetics have demonstrated that gender, mild or moderate renal impairment, Parkinson's disease stage and concomitant illnesses or the use of several common concomitant medications have no effect on the pharmacokinetics of ropinirole. Clearance is slower for patients older than 65 years compared with those who are younger, and in women taking hormone replacement therapy compared with those who are not. The CYP1A2 inhibitor ciprofloxacin produced increases in the plasma concentrations of ropinirole when these 2 drugs were coadministered, but no interaction was seen with theophylline which, like ropinirole, is also a substrate for CYP1A2. There is no obvious plasma concentration-effect relationship for ropinirole.

MEDICATION

Antiparkinson Agents; Dopamine Agonists

Use (kg; approx.) in Germany (2009): >75；Consumption (g per capita; approx.) in Germany (2009): 0.000916；Calculated removal (%): 11.8

For the treatment of the signs and symptoms of idiopathic Parkinson's disease. Also used for the treatment of restless legs syndrome.

The acid chloride of 2-(2-methyl-3-nitrophenyl)acetic acid is prepared with thionyl chloride, then treated with dipropylamine to form the amide. The carbonyl group is reduced with borane in THF and then reacted with diethyl oxalate and sodium in alcohol in a Claisen-type reaction to produce the ethyl ester of 3-[[2-(dipropylamino)ethyl]-6-nitrophenyl]pyruvic acid. Hydrolysis and decarboxylation of the acid with peroxide and base removes the ethoxycarbonyl group and forms 2-[2-(dipropylamino)ethyl]-6-nitrophenylacetic acid. Cyclization to the product is effected by catalytic reduction of the nitro group, using palladium/hydrogen to give the amine, which through loss of water forms the lactam (indolone). Heating with HCl forms ... /ropinirole hydrochloride/. /Ropinirole hydrochloride/

Preparation: G. Gallagher, Jr., United States of America patent 4452808 (1984 to SmithKline Beckman)