It was approved for medical use in the United States in 1997.[4] It is available as ageneric medication.[3] In 2023, it was the 212th most commonly prescribed medication in the United States, with more than 2million prescriptions.[6][7]
Ropinirole can cause nausea, dizziness, hallucinations,orthostatic hypotension, and sudden sleep attacks during the daytime. Unusual side effects specific to D3 agonists such as ropinirole andpramipexole can includehypersexuality,punding andcompulsive gambling, even in patients without a history of these behaviours.[10]
Ropinirole is also known to cause an effect known as "augmentation" when used to treat restless legs syndrome, where over time treatment with dopamine agonists will cause restless legs syndrome symptoms to become more severe. This usually leads to constant dosage increases in an attempt to offset the symptom progression. Symptoms will return to the level of severity they were experienced at before treatment was initiated if the drug is stopped; however, both ropinirole and pramipexole are known to cause painful withdrawal effects when treatment is stopped and the process of taking a patient who has been using the medication long-term off these drugs is often very difficult and should be supervised by a medical professional.[11]
Ropinirole produces markedhypolocomotion at lower doses (1–50mg/kg i.p.) and causeshyperlocomotion at higher doses (100mg/kg i.p.) in rodents.[23] The former effect is thought to be mediated by activation of inhibitorypresynaptic dopamineautoreceptors and reduced dopamine release, while the latter action is thought to be due to stimulation ofpostsynaptic dopamine receptors.[23] Activation of postsynaptic dopamine D2 receptors is thought to be involved in theantiparkinsonian effects of dopamine D2 receptor agonists like ropinrole.[23]
Major metabolitesin vivo formed by CYP1A2-mediated metabolism of ropinirole.
Ropinirole is metabolized primarily bycytochrome P450CYP1A2 to form twometabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted,[24] and at doses higher than clinical, is also metabolized byCYP3A4. At doses greater than 24 mg,CYP2D6 may be inhibited, although this has been tested onlyin vitro.[2]
7-Hydroxyropinirole (SK&F-89124), a majormetabolite of ropinirole in rats but minor metabolite in humans (<5% of dose), is a highly potent dopamine receptor agonist withantiparkinsonian activity similarly to ropinirole.[25][26][27][28][29] It has been reported to be 30-fold more potent than ropinirole as a dopamine D2 receptor agonistin vitro.[30][31] However, ropinirole and 7-hydroxyropinirole wereequipotent in terms of antiparkinsonian activity in rodentsin vivo.[29] 7-Hydroxyropinirole is said to be the only metabolite of ropinirole known to possess significant dopaminergic activityin vivo, although other ropinirole metabolites have also been found to have dopaminergic activity.[32][27][29]
In November 2012,GlaxoSmithKline was ordered by aRennes appeals court to pay Frenchman Didier Jambart 197,000 euros ($255,824); Jambart had taken ropinirole from 2003 to 2010 and exhibited risky hypersexual behavior and gambled excessively until stopping the medication.[42] This behavior displayed is characteristic ofDopamine Dysregulation Syndrome.[43]
^abcdTompson DJ, Vearer D (December 2007). "Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole: results of two randomized studies in patients with Parkinson's disease".Clinical Therapeutics.29 (12):2654–2666.doi:10.1016/j.clinthera.2007.12.010.PMID18201581.
^abcBritish National Formulary (76th ed.). Pharmaceutical Press. 2018. pp. 419–420.ISBN978-0-85711-338-2.
^Clinical trial numberNCT00334048 atClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
^Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, et al. (October 2008). "Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome".Sleep Med.9 (7):715–26.doi:10.1016/j.sleep.2007.11.020.PMID18226947.
^"What is Augmentation?"(PDF). Austin, Texas: Restless Legs Syndrome (RLS) Foundation. Archived fromthe original(PDF) on 9 May 2018. Retrieved8 May 2018.
^Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist".Pharmacology, Biochemistry, and Behavior.38 (1):147–154.doi:10.1016/0091-3057(91)90603-Y.PMID1673248.S2CID26842270.
^Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD (August 2023)."2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery".J Med Chem.66 (16):11027–11039.doi:10.1021/acs.jmedchem.3c01178.PMC11073569.PMID37584406.S2CID260924858.Functionally Biased Agonists. Conversely, a compound presenting as an agonist in 5-HT2B functional assays does not necessarily pose a risk for valvulopathy. In 5-HT2B calcium flux assays, certain known VHD-associated compounds displayed an agonist profile comparable to that of ropinirole, an approved treatment for Parkinson's disease (PD) and restless leg syndrome.122 Because ropinirole is not known to be associated with VHD or similar cardiopathies, it is thought that calcium flux may not be the optimal assay for screening 5-HT2B agonists for potential VHD-related risks. In additional readouts of 5-HT2B receptor activation (calcium-sensitive NFAT-mediated transcription of a β-lactamase reporter gene, accumulation of InsPs in LiCl-treated cells, recruitment of β-arrestin to agonist-occupied receptors, and phosphorylation of the extracellular signal-regulated kinase ERK2), ropinirole was found to be "distinct from the seven known valvulopathic 5- HT2B receptor agonists [studied] in that it is much less potent, albeit not less efficacious, than the VHD-associated drugs in all but one of the 5-HT2B receptor functional assays employed." 66
^Kvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists".Clin Ther.28 (8):1065–1078.doi:10.1016/j.clinthera.2006.08.004.PMID16982285.
^Kvernmo T, Houben J, Sylte I (2008). "Receptor-binding and pharmacokinetic properties of dopaminergic agonists".Curr Top Med Chem.8 (12):1049–1067.doi:10.2174/156802608785161457.PMID18691132.
^Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes".J Pharmacol Exp Ther.303 (2):791–804.doi:10.1124/jpet.102.039867.PMID12388666.
^Millan MJ, Cussac D, Gobert A, Lejeune F, Rivet JM, Mannoury La Cour C, et al. (June 2004). "S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: I. Cellular, electrophysiological, and neurochemical profile in comparison with ropinirole".J Pharmacol Exp Ther.309 (3):903–920.doi:10.1124/jpet.103.062398.PMID14978194.
^abOkano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S (February 2020)."Ropinirole, a New ALS Drug Candidate Developed Using iPSCs".Trends Pharmacol Sci.41 (2):99–109.doi:10.1016/j.tips.2019.12.002.PMID31926602.Before ROPI was first reported in 1985 [27], 7-hydroxyropinirole was identified as a highly potent dopamine agonist [28,29]. 7-Hydroxyropinirole has also been identified as a metabolite of ROPI in humans. [...] N,N-di-n-Propyldopamine is a lipophilic derivative of dopamine. By conversion of the monocyclic ring of N,N-di-n-propyldopamine to a bicyclic oxindole skeleton (bioisostere of phenol), 7-hydroxyropinirole was developed. Surprisingly, compared with that of N,N-di-npropyldopamine, the EC50 of 7-hydroxyropinirole for the dopamine D2 receptor (D2R) was greatly improved. ROPI does not have a 7-hydroxy group and its EC50 for D2R is higher than that of N,N-di-n-propyldopamine; nevertheless ROPI was ultimately selected as a clinical drug candidate.
^Ramji JV, Keogh JP, Blake TJ, Broom C, Chenery RJ, Citerone DR, et al. (March 1999). "Disposition of ropinirole in animals and man".Xenobiotica.29 (3):311–325.doi:10.1080/004982599238696.PMID10219970.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. [...] Brain extracts were shown to contain ropinirole and its 7-hydroxy metabolite (SK&F-89124 ; Figure 2). [...] In rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole (SK&F-89124). In mouse, monkey and man, the major pathway was via N-depropylation to form SK&F-104557, which was further metabolized, to a limited extent, to 7-hydroxy SK&F-104557 (SK&F-96990) and a carboxylic acid derivative of SK&F-104557 (SK&F-97930). Metabolites formed by either pathway were then generally metabolized further by glucuronidation in all species. SK&F-89124 is the only metabolite of ropinirole shown to possess significant dopamine agonist activity in an in vivo model of Parkinson's disease (Reavill et al., unpublished data).
^abContin M, Riva R, Albani F, Baruzzi A (2000)."Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease:".CNS Drugs.14 (6):439–455.doi:10.2165/00023210-200014060-00003.ISSN1172-7047.The major metabolic pathway in humans is via N-depropylation;[55] the N-despropyl metabolite accounts for 35 to 40% of the oral dose in human urine. 7-hydroxy ropinirole, the only metabolite of ropinirole that is thought to have significant dopamine agonist activity in vivo, [55] accounts for less than 5% of the dose. The potential contribution of 7-hydroxy ropinirole to the clinical effects of the parent drug is unknown.
^Hieble JP, Sulpizio AC, Sarau HM, Flaim KE, Blumberg AL, McCafferty JP, et al. (1989). "SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors".Fundam Clin Pharmacol.3 (6):621–642.doi:10.1111/j.1472-8206.1989.tb00464.x.PMID2575569.
^abcReavill C, Boyfield I, Coldwell M, Nelson P (September 2000). "Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats".J Pharm Pharmacol.52 (9):1129–1235.doi:10.1211/0022357001774895.PMID11045894.
^Hieble JP (1987). "Chapter 11 Peripheral Actions of Dopamine Receptor Agonists".Annual Reports in Medicinal Chemistry. Elsevier. p. 107–116.doi:10.1016/s0065-7743(08)61159-8.ISSN0065-7743.SK&F 101468 is hydroxylated vivo to form SK&F 89124, which is 30-fold more potent as a DA2 agonist (77); hence, although SK&F 101468 has intrinsic agonist activity at the DA2 receptor, being only two-fold less potent than dopamine as an inhibitor of adrenergic neurotransmission in the isolated rabbit ear artery (76), the majority of its in vivo activity may result from an active metabolite.
^Mico BA, Swagzdis JE, Federowicz DA, Straub K (October 1986). "Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone".J Pharm Sci.75 (10):929–933.doi:10.1002/jps.2600751003.PMID3795021.4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3~)-indolone was found in the plasma of rats, dogs, and monkeys treated with 3. As a D2-agonist, 1 is 30 times more potent than 3 in in vitro studies.1.3 The metabolism of 3 to 1 may contribute to the in vivo pharmacologic effect of 3. In dogs and monkeys (Figs. 5 and 6) the concentrations of 1 are about 10-fold lower than those of 3 and decline in parallel with 3.
^Deleu D, Northway MG, Hanssens Y (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease".Clin Pharmacokinet.41 (4):261–309.doi:10.2165/00003088-200241040-00003.PMID11978145.7-Hydroxy-ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo.
^Sit SY (August 2000). "Dopamine agonists in the treatment of Parkinson's disease past, present and future".Curr Pharm Des.6 (12):1211–1248.doi:10.2174/1381612003399581.PMID10903391.
^Clemens, J. A., Kornfeld, E. C., Phebus, L. A., Shaar, C. J., Smalstig, E. B., Cassady, J. M., ... & Kelly, E. (1982). Dopaminergic Agents Related to Ergolines. In The Chemical Regulation of Biological Mechanisms: The Proceedings of the 1st Medicinal Chemistry Symposium, Cambridge, England, 27th-30 September 1981 (Vol. 42, p. 167). London: Royal Society of Chemistry.https://archive.org/details/chemicalregulati0000medi/page/167/mode/1up
^David E. Nichols (29 June 1983)."The Development of Novel Dopamine Agonists".Dopamine Receptors. Vol. 224. Washington, D.C.: American Chemical Society. pp. 201–222.doi:10.1021/bk-1983-0224.ch009.ISBN978-0-8412-0781-3.The situation seems further confounded by the reports (13) of dopaminergic activity for the 4-substituted aminoethylindole DPAI, IX. However, the delayed onset of action reported by Cannon et al . (13) for this compound, as well as a weak in vitro action (14), lead to the possibility that DPAI may be metabolically activated by hydroxylation at the 6-position. This is a common transformation for indoles. Indeed, lergotrile is hydroxylated at the corresponding 13 position to yield a metabolite which is an order of magnitude more potent than lergotrile itself (15).
^Clemens JA, Fuller RW, Phebus LA, Smalstig EB, Hynes MD, Cassady JM, et al. (March 1984). "Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI)".Life Sci.34 (11):1015–1022.doi:10.1016/0024-3205(84)90014-6.PMID6422174.
^Gallagher G, Lavanchy PG, Webster CA, Wilson JW, Hieble JP, DeMarinis RM (October 1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: a prejunctional dopamine receptor agonist".J Med Chem.28 (10):1533–1536.doi:10.1021/jm00148a028.PMID4045928.
^Eden RJ, Wallduck MS, Patel B, Owen DA (January 1990). "Autonomic and haemodynamic responses to SK & F 101468 (ropinirole), a DA2 agonist, in anaesthetised cats".Eur J Pharmacol.175 (3):333–340.doi:10.1016/0014-2999(90)90572-n.PMID1969802.
^Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist".Pharmacol Biochem Behav.38 (1):147–154.doi:10.1016/0091-3057(91)90603-y.PMID1673248.
