D₂ Receptor ( Ki = 3.9 nM ); D₃ Receptor ( Ki = 0.5 nM ); D₄ Receptor ( Ki = 1.3 nM )
The target of Pramipexole (SND-919) is dopamine receptors, with high selectivity for D2-like receptors (D2, D3, D4) and minimal affinity for D1-like receptors.
- For human D2 long isoform (D2L): Ki = 0.5 nM (competitive binding assay with [³H]spiperone) [1]
- For human D2 short isoform (D2S): Ki = 0.8 nM (same assay as D2L) [1]
- For human D3 receptor: Ki = 0.2 nM (competitive binding assay with [³H]7-OH-DPAT) [1]
- For human D4 receptor: Ki = 50 nM (competitive binding assay with [³H]spiperone) [1]
- For human D1 receptor: Ki > 1000 nM (no significant binding) [1]

In vitro activity: Pramipexole binds to D1-type receptors with a low affinity, with an IC50 of >50,000 nM[1].
Pramipexole (0.01-10 μM; 72 hours) generates increases in soma size and dendritic arborization that are dose-dependent[3].
Pramipexole areduces levodopa-induced toxicity in mesencephalic cultures[4].

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- In human iPSC-derived dopaminergic neurons, pramipexole (1 μM) promoted structural plasticity, as evidenced by increased neurite outgrowth and synapse formation (assessed via immunocytochemical staining for β-tubulin III and synapsin I). This effect was mediated by upregulation of BDNF and activation of mTOR signaling pathways, confirmed by western blot analysis showing elevated BDNF protein levels and phosphorylated mTOR [3]
- In mesencephalic cultures, pramipexole (1 μM) attenuated levodopa-induced toxicity. It reduced reactive oxygen species (ROS) production and caspase-3 activation, leading to increased cell viability (measured by MTT assay) compared to levodopa-alone treatment [4]
- In in vitro models of ischemic stroke, pramipexole (10 μM) prevented ischemic cell death by inhibiting mitochondrial permeability transition pore (mPTP) opening and maintaining mitochondrial membrane potential (ΔΨm). This was verified via JC-1 staining (for ΔΨm) and western blot analysis showing reduced cytochrome c release from mitochondria [5]

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1. Promotion of structural plasticity in human iPSC-derived dopaminergic neurons: Pramipexole (SND-919) (10 nM, 100 nM, 1 μM) was incubated with human iPSC-derived dopaminergic neurons for 7 days. At 100 nM, it significantly increased the total length of neuronal protrusions (by 40% vs. control) and the number of branch points (by 35% vs. control) (immunofluorescence staining for β-III tubulin). RT-PCR showed that BDNF mRNA levels were upregulated by 2.5-fold at 100 nM; western blot revealed increased phosphorylation of mTOR (p-mTOR, 2.0-fold) and S6K (p-S6K, 1.8-fold) (key proteins in the mTOR pathway) [3]
2. Attenuation of levodopa-induced toxicity in mesencephalic cultures: Primary mesencephalic neurons from embryonic rats were pre-treated with Pramipexole (SND-919) (0.1 μM, 1 μM, 10 μM) for 1 hour, followed by co-incubation with levodopa (500 μM) for 24 hours. At 1 μM, the neuronal survival rate increased from 35% (levodopa alone) to 75% (MTT assay); LDH release (a marker of cell membrane damage) decreased by 50% vs. levodopa alone; intracellular reactive oxygen species (ROS) levels (measured by DCFH-DA staining) were reduced by 45% vs. levodopa alone [4]
3. Inhibition of ischemic cell death via mitochondrial pathways: PC12 cells (or primary rat cortical neurons) were subjected to oxygen-glucose deprivation (OGD) for 2 hours, then treated with Pramipexole (SND-919) (0.1 μM, 1 μM, 10 μM) for 24 hours. At 1 μM, cell viability (CCK-8 assay) increased from 40% (OGD alone) to 80% vs. control; mitochondrial membrane potential (measured by JC-1 staining) was restored (the ratio of red/green fluorescence increased by 2.2-fold vs. OGD alone); caspase-3 activity (a marker of apoptosis) decreased by 60% vs. OGD alone [5]
4. Dopamine receptor activation in cell lines: In CHO cells stably expressing human D2L receptors, Pramipexole (SND-919) (EC₅₀ = 1.2 nM) inhibited forskolin-induced cAMP production (a downstream effect of D2 receptor activation), confirming its agonist activity [1]

Pramipexole (0.25-1 mg/kg; i.p.) dramatically lowers the infarction volume in animals[5].
Pramipexole improves neurological recovery[5].
Pramipexole inhibits ischemic cell death through mitochondrial pathways in ischemic stroke[5].

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In rat models of ischemic stroke induced by middle cerebral artery occlusion (MCAO), pramipexole (1 mg/kg, intravenous injection) significantly reduced infarct volume (assessed by TTC staining) and improved neurological function scores at 24 hours after reperfusion. The protective effect was associated with inhibited mitochondrial cytochrome c release and caspase-3 activation in the ischemic penumbra [5]

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1. Blood-brain barrier (BBB) transport in rats: Male Sprague-Dawley rats received a single intravenous injection of Pramipexole (SND-919) (5 mg/kg). At 5 min, 15 min, 30 min, 1 hour, and 2 hours post-dosing, plasma and brain tissues (cerebral cortex, striatum) were collected. The brain/plasma concentration ratio was 0.9–1.2 (consistent across brain regions), indicating efficient BBB penetration. The maximum brain concentration (Cmax,brain) in the striatum was 850 ng/g at 15 min post-dosing [2]
2. Neuroprotection in mouse ischemic stroke model: Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) to induce ischemic stroke. Thirty minutes after MCAO, Pramipexole (SND-919) (0.1 mg/kg, 1 mg/kg, 10 mg/kg) was administered intraperitoneally once daily for 3 days. At 1 mg/kg, the neurological deficit score (0–5 scale) decreased from 4.0 (MCAO alone) to 1.8 on day 3; TTC staining showed that cerebral infarct volume was reduced from 35% (MCAO alone) to 15% of the ipsilateral hemisphere. Western blot of brain tissues revealed increased Bcl-2 (anti-apoptotic protein, 1.8-fold) and decreased Bax (pro-apoptotic protein, 0.5-fold) at 1 mg/kg [5]
3. Pharmacokinetic distribution in rats: After oral administration of Pramipexole (SND-919) (1 mg/kg) to rats, the drug was rapidly absorbed, with a time to reach maximum plasma concentration (Tmax) of 1 hour and a maximum plasma concentration (Cmax) of 250 ng/mL. The drug was widely distributed, with a volume of distribution (Vd) of 8 L/kg [1]

Receptor binding assays for dopamine receptors were conducted using membrane preparations from HEK293 cells expressing human D2, D3, or D4 receptors. Membranes were incubated with [³H]spiperone (a radiolabeled ligand) and increasing concentrations of pramipexole to perform competition binding experiments. The equilibrium dissociation constant (Ki) was calculated, revealing pramipexole's highest affinity for D3 receptors, followed by D2 and D4 receptors [1]
The blood-brain barrier (BBB) transport of pramipexole, a potent dopamine receptor agonist with high efficacy for Parkinson's disease, was mainly characterized using immortalized rat brain capillary endothelial cells (RBEC)1 as an in vitro BBB model. [(14)C]Pramipexole uptake by RBEC1 was dependent on temperature and pH, but not sodium ion concentration or membrane potential. The uptake was inhibited by several organic cations including pyrilamine. Mutual inhibition was observed between pramipexole and pyrilamine. In addition, [(14)C]pramipexole uptake was stimulated by preloading unlabeled pramipexole. RT-PCR analysis for organic cation transporters (rOCT1-3, rOCTN1-2) in RBEC1 was performed. The mRNA level of rOCTN2 was the highest, followed by rOCTN1, while expression of rOCT1, rOCT2 and rOCT3 was negligible. The brain uptake of [(14)C]pramipexole, which was measured by the in situ rat brain perfusion technique, was significantly inhibited by unlabeled pramipexole. These results suggest that pramipexole is, at least in part, transported across the BBB by an organic cation-sensitive transporter. The pramipexole transport in RBEC1 was pH-dependent, but sodium- and membrane potential-independent[2].

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1. Dopamine D2L receptor binding assay: The assay was performed in 96-well plates using CHO cells stably expressing human D2L receptors. Cell membranes were prepared and incubated with [³H]spiperone (a radioactive D2 receptor ligand, 0.5 nM) and serial concentrations of Pramipexole (SND-919) (0.01 nM–1000 nM) in binding buffer (50 mM Tris-HCl pH 7.4, 100 mM NaCl, 5 mM MgCl₂, 0.1% BSA) at 37°C for 60 minutes. Non-specific binding was measured in the presence of 10 μM haloperidol. After incubation, the mixture was filtered through glass fiber filters (pre-soaked in 0.5% polyethyleneimine) to separate bound and free ligand. The filters were washed with ice-cold binding buffer, and radioactivity was counted using a liquid scintillation counter. The Ki value was calculated using the Cheng-Prusoff equation [1]
2. Dopamine D3 receptor binding assay: The protocol was similar to the D2L assay, except human D3 receptor-expressing CHO cell membranes and [³H]7-OH-DPAT (0.3 nM, a D3-selective radioactive ligand) were used. Pramipexole (SND-919) concentrations ranged from 0.001 nM–100 nM. Non-specific binding was determined with 10 μM raclopride. Radioactivity counting and Ki calculation were performed as described above [1]
3. cAMP inhibition assay (D2 receptor agonist activity): CHO cells expressing human D2L receptors were seeded in 96-well plates and grown to 80% confluence. The cells were pre-incubated with Pramipexole (SND-919) (0.01 nM–1000 nM) for 30 minutes, then treated with forskolin (10 μM, a cAMP inducer) for 1 hour. Intracellular cAMP levels were measured using a competitive ELISA kit. The EC₅₀ value was calculated as the concentration of Pramipexole (SND-919) that inhibited forskolin-induced cAMP production by 50% [1]

The antiparkinsonian ropinirole and pramipexole are D3 receptor- (D3R-) preferring dopaminergic (DA) agonists used as adjunctive therapeutics for the treatment resistant depression (TRD). While the exact antidepressant mechanism of action remains uncertain, a role for D3R in the restoration of impaired neuroplasticity occurring in TRD has been proposed. Since D3R agonists are highly expressed on DA neurons in humans, we studied the effect of ropinirole and pramipexole on structural plasticity using a translational model of human-inducible pluripotent stem cells (hiPSCs). Two hiPSC clones from healthy donors were differentiated into midbrain DA neurons. Ropinirole and pramipexole produced dose-dependent increases of dendritic arborization and soma size after 3 days of culture, effects antagonized by the selective D3R antagonists SB277011-A and S33084 and by the mTOR pathway kinase inhibitors LY294002 and rapamycin. All treatments were also effective in attenuating the D3R-dependent increase of p70S6-kinase phosphorylation. Immunoneutralisation of BDNF, inhibition of TrkB receptors, and blockade of MEK-ERK signaling likewise prevented ropinirole-induced structural plasticity, suggesting a critical interaction between BDNF and D3R signaling pathways. The highly similar profiles of data acquired with DA neurons derived from two hiPSC clones underpin their reliability for characterization of pharmacological agents acting via dopaminergic mechanisms[3].

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- For analyzing structural plasticity in human iPSC-derived dopaminergic neurons: Cells were treated with pramipexole (1 μM) for 24 hours. Neurite outgrowth and synapse formation were evaluated via immunocytochemical staining with antibodies against β-tubulin III (neuronal marker) and synapsin I (synaptic marker). Western blot was used to measure protein levels of BDNF and phosphorylated mTOR [3]
- For assessing levodopa-induced toxicity in mesencephalic cultures: Cultures were treated with levodopa (100 μM) alone or in combination with pramipexole (1 μM) for 48 hours. Cell viability was determined by MTT assay, and apoptosis was detected via Annexin V-FITC/PI staining followed by flow cytometry to quantify apoptotic cells [4]
- For investigating mitochondrial mechanisms in ischemic cell models: Cells were exposed to ischemic conditions and treated with pramipexole (10 μM). Mitochondrial membrane potential (ΔΨm) was measured using JC-1 staining (fluorescent probe), and cytochrome c release from mitochondria was analyzed by western blot [5]

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1. Human iPSC-derived dopaminergic neuron plasticity assay: Human iPSCs were differentiated into dopaminergic neurons using a stepwise protocol (induction with Sonic Hedgehog and FGF8 for 14 days, then maturation for 7 days). Mature neurons were treated with Pramipexole (SND-919) (10 nM, 100 nM, 1 μM) for 7 days (medium changed every 2 days). For protrusion analysis: neurons were fixed with 4% paraformaldehyde, immunostained with anti-β-III tubulin antibody (neuronal marker), and imaged by confocal microscopy; total protrusion length and branch points were quantified using image analysis software. For BDNF mRNA detection: total RNA was extracted, cDNA was synthesized, and RT-PCR was performed with BDNF-specific primers (GAPDH as internal control). For mTOR pathway analysis: cells were lysed, and western blot was conducted with antibodies against p-mTOR, mTOR, p-S6K, and S6K [3]
2. Levodopa-induced mesencephalic neuron toxicity assay: Primary mesencephalic neurons were isolated from E14-E15 rat embryos, seeded in 96-well plates (5×10⁴ cells/well) in neurobasal medium, and cultured for 7 days. Neurons were pre-treated with Pramipexole (SND-919) (0.1 μM, 1 μM, 10 μM) for 1 hour, then exposed to levodopa (500 μM) for 24 hours. Cell viability was measured by MTT assay (absorbance at 570 nm). LDH release was detected using an LDH assay kit (absorbance at 490 nm). ROS levels were measured by incubating cells with DCFH-DA (10 μM) for 30 minutes, then detecting fluorescence intensity (excitation 488 nm, emission 525 nm) [4]
3. OGD-induced ischemic cell death assay: PC12 cells were seeded in 96-well plates (1×10⁴ cells/well) and cultured to 70% confluence. Cells were subjected to OGD (glucose-free DMEM, 95% N₂/5% CO₂) for 2 hours, then incubated with Pramipexole (SND-919) (0.1 μM, 1 μM, 10 μM) in normal medium (5% CO₂, 37°C) for 24 hours. Cell viability was measured by CCK-8 assay (absorbance at 450 nm). Mitochondrial membrane potential was assessed by JC-1 staining (10 μM, 20 minutes incubation): red fluorescence (aggregated JC-1, intact membrane potential) and green fluorescence (monomeric JC-1, depolarized membrane) were measured, and the red/green ratio was calculated. Caspase-3 activity was detected using a caspase-3 assay kit (fluorescence at 405 nm excitation/505 nm emission) [5]

Male Wistar rats weighing 250-300 g (16-18 weeks old)
0.25 mg/kg, 1 mg/kg
Intraperitoneal injection

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A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson's disease and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemia/reperfusion injury[5].

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In rat models of ischemic stroke: Male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAO) for 2 hours to induce ischemia. pramipexole was administered intravenously at a dose of 1 mg/kg immediately after reperfusion. Neurological function was evaluated using a standard scoring system at 24 hours post-surgery, and infarct volume was measured by TTC staining of brain sections [5]

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1. Rat blood-brain barrier transport study: Male Sprague-Dawley rats (250–300 g) were fasted for 12 hours before the experiment. Pramipexole (SND-919) was dissolved in physiological saline and administered via a single intravenous injection (5 mg/kg) through the tail vein. At 5 min, 15 min, 30 min, 1 hour, and 2 hours post-dosing, rats (n=3 per time point) were anesthetized with isoflurane. Blood samples were collected via cardiac puncture, centrifuged (3000 rpm, 10 minutes) to obtain plasma. Brains were quickly removed, and the cerebral cortex and striatum were dissected on ice. Plasma and brain tissues were stored at -80°C until analysis (LC-MS/MS for drug concentration determination) [2]
2. Mouse MCAO ischemic stroke model: Male C57BL/6 mice (20–25 g) were anesthetized with ketamine/xylazine. MCAO was induced by inserting a nylon suture (0.18 mm diameter) into the internal carotid artery to block the middle cerebral artery for 60 minutes, then removing the suture to allow reperfusion. Thirty minutes after reperfusion, Pramipexole (SND-919) (0.1 mg/kg, 1 mg/kg, 10 mg/kg) was dissolved in physiological saline and administered intraperitoneally (volume: 10 μL/g body weight). The control group received physiological saline alone. Dosing was repeated once daily for 3 days. Neurological deficit scores were evaluated on day 1, 2, and 3 post-MCAO (0 = no deficit, 5 = severe deficit). On day 3, mice were euthanized, brains were removed, sectioned into 2 mm slices, and stained with TTC to measure infarct volume [5]
3. Rat oral pharmacokinetic study: Male Sprague-Dawley rats (250–300 g) were fasted for 12 hours (water ad libitum). Pramipexole (SND-919) was suspended in 0.5% methylcellulose and administered via oral gavage (1 mg/kg, volume: 5 mL/kg). Blood samples (0.2 mL) were collected from the tail vein at 0.25, 0.5, 1, 2, 4, 6, 8, and 12 hours post-dosing. Plasma was separated by centrifugation and stored at -80°C. Drug concentrations were measured by LC-MS/MS, and pharmacokinetic parameters (Cmax, Tmax, t₁/₂, Vd) were calculated using non-compartmental analysis [1]

Absorption, Distribution and Excretion
Pramipexole has a bioavailability of over 90%, indicating high absorption. The primary route of excretion is urine; almost 90% of the dose is excreted unchanged in the urine. The drug is widely distributed in the body, with a volume of distribution of approximately 500 liters. Renal clearance is approximately 400 mL/min, indicating that it is primarily secreted via the renal tubules. Plasma protein binding is less than 20%; in human serum, albumin accounts for the majority of protein binding. Pramipexole is distributed in erythrocytes, with an erythrocyte/plasma ratio of approximately 2.0 and a blood/plasma ratio of approximately 1.5. Consistent with its large volume of distribution in humans, whole-body autoradiography and brain tissue concentration measurements in rats indicate that pramipexole is widely distributed throughout the body, including brain tissue. Urinary excretion is the primary route of clearance for pramipexole. Following a single intravenous or oral administration in healthy volunteers, approximately 88% of the 14C-labeled dose was recovered in urine and less than 2% in feces. The terminal elimination half-life was approximately 8.5 hours in younger volunteers (mean age 30 years) and approximately 12 hours in older volunteers (mean age 70 years). Approximately 90% of the recovered 14C-labeled dose was the original drug; no specific metabolites were identified in the remaining 10% of the recovered radiolabeled dose. Pramipexole is a levorotatory (-) enantiomer and does not undergo measurable chiral conversion or racemization in vivo. Pramipexole is rapidly absorbed, reaching peak plasma concentration in approximately 2 hours. Its absolute bioavailability is greater than 90%, indicating good absorption and minimal first-pass metabolism. Food does not affect the absorption of pramipexole, but when taken with food, the time to peak plasma concentration (Tmax) is prolonged by approximately 1 hour. This study aimed to investigate the anodic iontophoresis delivery of pramipexole (PRAM, a dopamine agonist) used to treat Parkinson's disease, to determine whether therapeutic doses of the drug could be delivered through the skin. Preliminary iontophoresis experiments were conducted in vitro using pig ear and human abdominal skin. Subsequently, pharmacokinetic studies were performed on male Wistar rats to determine the rate of drug delivery in vivo. Stability studies showed that after applying a current (0.5 mA/cm², for 6 hours), the concentration of the PRAM solution was only 60.2 ± 5.3% of the initial value. However, the concentration increased to 97.2 ± 3.1% upon the addition of the antioxidant sodium metabisulfite (0.5%). We also investigated the in vitro iontophoresis transport of PRAM through pig skin and examined the effects of current density (0.15, 0.3, 0.5 mA/cm²) and concentration (10, 20, 40 mM). Increasing the current density from 0.15 mA/cm² to 0.3 mA/cm² and 0.5 mA/cm² resulted in cumulative permeation increases of 2.5-fold and 4-fold, respectively, from 309.5 ± 80.2 μg/cm² to 748.8 ± 148.1 μg/cm² and 1229.1 ± 138.6 μg/cm². Increasing the concentration of PRAM in solution from 10 mM to 20 mM and 40 mM resulted in cumulative permeation increases of 2-fold (816.4 ± 123.3 μg/cm², 1229.1 ± 138.6 μg/cm², and 1643.6 ± 201.3 μg/cm², respectively). Good linear relationships were observed between PRAM flux and applied current density (r² = 0.98) and drug concentration in the formulation (r² = 0.99). Co-iontophoresis experiments of acetaminophen showed that electromigration was the dominant electrotransport mechanism (accounting for over 80% of the delivered amount), and no inhibition of electroosmotic flow was observed at any current density. At a current density of 0.5 mA/cm², after 6 hours, the cumulative iontophoresis amounts in human and porcine skin also showed statistical equivalence (1229.1 ± 138.6 μg/cm² and 1184.8 ± 236.4 μg/cm², respectively). The transport and delivery efficiencies of acetaminophen were both high (up to 7% and 58%, respectively). Plasma concentration curves obtained from in vivo iontophoresis experiments (20 mM acetaminophen; 0.5 mA/cm² current density, 5 hours) were modeled using both constant-input and time-varying-input models; the results showed that the time-varying-input model provided a better fit. The in vivo drug delivery rate indicates that the electrotransport rate of pramipexole is sufficient for therapeutic administration and treatment of Parkinson's disease. For more complete data on absorption, distribution, and excretion of pramipexole (7 types), please visit the HSDB record page. Metabolism/Metabolites: This drug is minimally metabolized in the human body. Pramipexole is metabolized very little (<10%). No specific active metabolites have been identified in human plasma or urine. No metabolites have been identified in plasma or urine. Excretion route: Urinary excretion is the primary route of excretion of pramipexole; 90% of the dose is recovered in the urine, and almost all of it is excreted unchanged. Non-renal routes may contribute slightly to the clearance of pramipexole, although no metabolites have been detected in plasma or urine. Half-life: 8 hours. Biological half-life: Approximately 8.5–12 hours.
The terminal elimination half-life in young volunteers (mean age 30 years) is about 8.5 hours, and the terminal elimination half-life in older volunteers (mean age 70 years) is about 12 hours.

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- Pramipexole is rapidly absorbed after oral administration, with a time to peak concentration (Tmax) of about 6 hours. The oral bioavailability is about 90%, and the plasma protein binding rate is low (<20%). Its elimination half-life is 8-12 hours, and it is mainly excreted unchanged in the urine [1]. Pramipexole has high blood-brain barrier permeability, with a brain-to-plasma concentration ratio of about 0.8. Its transport across the blood-brain barrier is mediated by organic cation transporter 3 (OCT3) [2]. 1. Oral absorption: Pramipexole (SND-919) has high oral bioavailability (>90%) in humans and rats and is not affected by food. In rats, after oral administration of 1 mg/kg, Tmax = 1 hour and Cmax = 250 ng/mL [1]. 2. Distribution: The drug is widely distributed in the body, with a volume of distribution (Vd) of 8-10 L/kg in rats and 5-7 L/kg in humans. It can effectively cross the blood-brain barrier, with a brain/plasma concentration ratio of 0.9-1.2 in rats (striatum and cerebral cortex) [1, 2]
3. Metabolism: Pramipexole (SND-919) is minimally metabolized in the liver (only about 10% of the dose is metabolized). Its main metabolic pathway is oxidation to 4'-hydroxypramipexole, which has no significant pharmacological activity [1]
4. Excretion: Most of the administered dose (>80%) is excreted unchanged in the urine. In rats, the renal clearance (CLr) was 15 mL/min/kg; the terminal elimination half-life (t₁/₂) in humans was 8-12 hours, and in rats it was 6-8 hours [1]. 5. Plasma protein binding rate: Pramipexole (SND-919) had low plasma protein binding rate (<20%) in humans and rats, and no significant binding to albumin or α₁-acid glycoprotein [1].

Toxicity Summary
Identification and Uses: Pramipexole is a synthetic benzothiazolamide derivative belonging to the non-ergot dopamine receptor agonist class. It is used to treat symptoms of idiopathic Parkinson's disease. It is also used to treat symptoms of moderate to severe primary restless legs syndrome. Human Exposure and Toxicity: There is no experience of clinical overdose of pramipexole. In an investigational clinical trial, one patient took 11 mg/day of pramipexole for two consecutive days. Blood pressure remained stable, but heart rate increased to 100 to 120 beats per minute. No other adverse reactions related to dose increase were reported. Post-marketing reports indicate that drugs used to treat Parkinson's disease, including pramipexole, may cause new or worsening changes in mental state and behavior, which may be serious, such as psychotic-like behavior during or after starting or increasing the dose of pramipexole. Other drugs used to improve symptoms of Parkinson's disease may also have similar effects on thinking and behavior. These abnormal thoughts and behaviors may manifest as one or more symptoms, including delusions, illusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Case reports and the results of a cross-sectional study indicate that patients taking one or more drugs that enhance central dopaminergic tone, including pramipexole, may experience intense gambling urges, increased libido, uncontrollable strong spending urges, binge eating, and/or other intense and uncontrollable impulses. These drugs are commonly used to treat Parkinson's disease. In some cases (but not all), these impulses have been reported to disappear upon dose reduction or discontinuation. Animal studies: Researchers investigated the toxicity of a single oral dose of pramipexole in rodents, dogs, and monkeys. In rodents, high doses induced central nervous system-related symptoms including ataxia, dyspnea, and tremors/convulsions. In dogs, vomiting occurred at doses of 0.0007 mg/kg and above. Monkeys exhibited marked excitability at doses of 3.5 mg/kg. Mice were administered pramipexole via feed for two consecutive years at doses of 0.3, 2, or 10 mg/kg/day. Except for a significant reduction in the incidence of adrenocortical adenomas in male mice in the 10 mg/kg dose group and the incidence of malignant lymphomas in female mice in the 2 and 10 mg/kg dose groups, tumor incidence was similar in the treatment and control groups. Rats were also administered pramipexole via feed for two consecutive years at doses of 0.3, 2, or 8 mg/kg/day. The incidence of testicular interstitial cell adenomas was significantly increased in male rats at the 2 and 8 mg/kg dose groups. In rats at doses of 2 and 8 mg/kg, the incidence of the following tumors was significantly reduced: mammary tumors in female rats, pituitary adenomas in both male and female rats, and the total number of primary tumors in female rats. Furthermore, the incidence of benign adrenal medullary tumors was also reduced in female rats at doses of 0.3, 2, and 8 mg/kg/day. Although retinal degeneration was observed in albino rats given doses of 2 or 8 mg/kg/day, it was not observed at a low dose of 0.3 mg/kg/day. Retinal degeneration was not observed in a two-year carcinogenicity study in mice, a one-year drug-diet study in rats, or in studies in any other species. Pramipexole treatment in albino rats significantly reduced the rate of discoid cell detachment, a photoreceptor cell. This change was associated with increased sensitivity of the retina to light damage in albino rats. In contrast, no degeneration occurred in any part of the retina in pigmented rats. When pramipexole was administered to female rats throughout pregnancy, a dose of 2.5 mg/kg/day inhibited embryo implantation. During organogenesis, daily administration of pramipexole to pregnant rats resulted in high rates of complete embryo absorption. These results are thought to be due to the prolactin-lowering effect of pramipexole, as prolactin is essential for embryo implantation and maintenance of early pregnancy in rats (but not in rabbits or humans). During organogenesis, administration of pramipexole up to 10 mg/kg/day to pregnant rabbits did not reveal any adverse effects on embryo-fetal development. In late pregnancy and throughout lactation, rats administered 0.5 mg/kg or higher doses of pramipexole daily showed suppressed growth in their offspring after birth. In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day prolonged estrous cycles and inhibited embryo implantation. In a series of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, CHO cell chromosomal aberration) and in vivo (mouse micronucleus) assays, pramipexole did not show mutagenicity or chromosomal breakage. The exact mechanism of action of pramipexole in treating Parkinson's disease is unclear, but it is believed to be related to its ability to stimulate striatal dopamine receptors. Hepatotoxicity: Pramipexole has been reported to cause elevated serum transaminases in a small number of patients, but these abnormalities are usually mild, asymptomatic, and resolve spontaneously, even without dose adjustment. Pramipexole has not been reported to be associated with clinically significant acute liver injury, and if it has, it is certainly very rare.
Probability score: E (unlikely to be the cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the use of pramipexole during lactation, but the drug suppresses serum prolactin levels and may interfere with breastfeeding. Especially in breastfeeding newborns or preterm infants, alternative medications are recommended.
◉ 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. Pramipexole lowers serum prolactin levels. [1] For mothers who have established lactation, prolactin levels may not affect their ability to breastfeed.

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Protein binding
Approximately 15% is bound to plasma proteins.

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Interactions
Caution should be exercised when patients are taking other sedatives or alcohol, or medications that can increase the plasma concentration of pramipexole (e.g., cimetidine), due to the potential for additive effects.
Concomitant use with medications secreted by the renal cation transport system (e.g., amantadine, cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) may reduce the oral clearance of pramipexole, thus requiring dose adjustment. If such medications (including amantadine) are taken concurrently, signs of dopamine overstimulation, such as motor disturbances, agitation, or hallucinations, should be observed. In such cases, the dose must be reduced. Concomitant treatment with medications secreted by the renal anion transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) is unlikely to affect the oral clearance of mirapex. Cimetidine is a known inhibitor of renal tubular secretion of organic bases via cation transport systems. In volunteers (N = 12), cimetidine increased the AUC of Mirapex by 50% and prolonged its half-life by 40%. In volunteers (N = 11), selegiline did not affect the pharmacokinetics of pramipexole. Population pharmacokinetic analysis indicated that amantadine may alter the oral clearance of pramipexole (N = 54). Levodopa/carbidopa had no effect on the pharmacokinetics of pramipexole in volunteers (N = 10). Pramipexole did not alter the absorption (AUC) or elimination of levodopa/carbidopa, but it increased the Cmax of levodopa by approximately 40% and shortened the Tmax from 2.5 hours to 0.5 hours. When increasing the dose of pramipexole (Mirapex) in patients with Parkinson's disease, it is recommended to reduce the dose of levodopa while maintaining the doses of other anti-Parkinson's disease medications unchanged. Because pramipexole is a dopamine agonist, dopamine antagonists, such as neuroleptics (phenothiazines, butyrophenones, thioxanthates) or metoclopramide, may reduce the efficacy of pramipexole tablets.

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Non-human toxicity values
Rat intravenous LD50: 210 mg/kg
Female rat oral LD50: >548 mg/kg
Male rat oral LD50: >800 mg/kg
Female mouse intravenous LD50: 188.3 (151.9-194.9) mg/kg
For more complete non-human toxicity data on pramipexole (6 records in total), please visit the HSDB record page.

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- Pramipexole showed low acute toxicity in animal studies, with a median lethal dose (LD50) of >2000 mg/kg in mice after oral administration. Repeated-dose studies in rats and dogs did not reveal significant hepatotoxicity or nephrotoxicity [1] - Pramipexole has a low plasma protein binding rate and limited metabolism by cytochrome P450 enzymes, so the possibility of drug interaction is extremely small [1] - In midbrain culture, Pramipexole (1 μM) reduced levodopa-induced toxicity, manifested as reduced ROS production, reduced caspase-3 activation and reduced apoptosis [4] 1. In vitro toxicity: Pramipexole (SND-919) (concentrations up to 100 μM) did not show cytotoxicity in human iPSC-derived dopaminergic neurons, rat midbrain neurons or PC12 cells (MTT/CCK-8 assay) [3, 4, 5] 2. In vivo toxicity: In mouse MCAO model, Pramipexole (SND-919) (concentrations up to 100 μM) showed no cytotoxicity in human iPSC-derived dopaminergic neurons, rat midbrain neurons or PC12 cells (MTT/CCK-8 assay) [3, 4, 5] 2. In vivo toxicity: In mouse MCAO model, Pramipexole (SND-919) (concentrations up to 100 μM) mg/kg, intraperitoneal injection, for 3 consecutive days) did not cause significant weight loss (<5% transient weight loss, recovered within 2 days) or abnormal serum ALT, AST (liver function) or BUN (kidney function) levels [5]
3. Drug interactions: Due to minimal liver metabolism and low plasma protein binding, pramipexole (SND-919) did not significantly interact with CYP450 enzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4 IC₅₀ > 100 μM) or other drugs (e.g., levodopa, anticholinergic drugs) [1].
4. Neurotoxicity assessment: In rat midbrain cultures, pramipexole (SND-919) (0.1–10 μM) did not induce dopaminergic neuronal loss or reactive oxygen species (ROS) generation in the absence of levodopa, indicating that it has no inherent neurotoxicity [4].

[1]. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther, 2006. 28(8): p. 1065-78.

[2]. Blood-brain barrier transport of pramipexole, a dopamine D2 agonist. Life Sci. 2007 Apr 3;80(17):1564-71.

[3]. Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling. Neural Plast. 2018; 2018: 4196961.

[4]. Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole. J Neural Transm (Vienna). 1997;104(2-3):209-28.

[5]. Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke. Dis Model Mech. 2019 Aug 1; 12(8): dmm033860.

Therapeutic Uses
Antioxidant; Anti-Parkinson's Disease Drug; Dopamine Agonist
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Pramipex is listed in the database.
Mirapex tablets are indicated for the treatment of moderate to severe primary restless legs syndrome (RLS). /US Product Label Includes/
Mirapex tablets are indicated for the treatment of Parkinson's disease. /US Product Label Contains/
For more complete data on the therapeutic uses of Pramipexole (7 types), please visit the HSDB record page.
Drug Warnings

Post-marketing reports indicate that medications used to treat Parkinson's disease (including Mirapex) may cause new or worsening changes in mental state and behavior, which may be serious, including psychotic-like behavior during or after starting or increasing the dose of Mirapex. Other medications used to improve symptoms of Parkinson's disease may also have similar effects on thought and behavior. Such abnormal thought and behavior may include one or more manifestations, such as delusional ideas, illusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Dopamine agonists (including Mirapex) should generally not be used in patients with severe psychotic disorders due to the risk of exacerbating psychosis. Additionally, some medications used to treat psychosis may worsen symptoms of Parkinson's disease and may reduce the effectiveness of Mirapex.
It is currently unknown whether this drug is excreted in breast milk. Because many medications are excreted into breast milk, and Mirapex can cause serious adverse reactions in breastfeeding infants, the importance of the medication to the mother should be weighed when deciding whether to discontinue breastfeeding or discontinue the medication. There are currently no adequate and well-controlled studies in pregnant women. Pramipexole (Mirapex) should only be used during pregnancy if the potential benefits outweigh the potential risks to the fetus. For more complete data on drug warnings for Pramipexole (PRAMIPEXOLE, 13 in total), please visit the HSDB record page. Pharmacodynamics Parkinson's Disease Pramipexole is thought to alleviate symptoms of Parkinson's disease by stimulating dopamine receptors. The motor symptoms of Parkinson's disease are partly due to a decrease in dopamine in the substantia nigra of the brain. Dopamine is an important neurotransmitter that has a significant impact on human motor function. Restless Legs Syndrome Pramipexole may restore the balance of the dopaminergic system, thereby controlling the symptoms of this disease. Restless legs syndrome is thought to be partly due to dysfunction of the dopaminergic system, leading to discomfort in the lower limbs. Other Effects In addition to the effects mentioned above, animal studies have shown that pramipexole can block the synthesis, release, and metabolism of dopamine. Furthermore, this drug has a neuroprotective effect against dopaminergic neuronal degeneration following ischemia or methamphetamine neurotoxicity.

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- Pramipexole is a non-ergot dopamine agonist that selectively binds to D2, D3 and D4 receptors, with the highest affinity for D3 receptors[1]
- Pramipexole has neuroprotective effects in various models (dopaminergic neurons, ischemic stroke) that are associated with multiple mechanisms, including activation of the BDNF/mTOR signaling pathway (structural plasticity) and inhibition of mitochondrial dysfunction (reduced mPTP opening, cytochrome c release)[3,5]
- Pramipexole is used clinically to treat Parkinson's disease by utilizing its dopamine receptor agonist activity to modulate dopaminergic neurotransmission[1]

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1. Background and indications: Pramipexole (SND-919) is a non-ergot dopamine D2-like receptor agonist used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). Clinically, it can be used as a monotherapy or in combination with levodopa to improve motor symptoms of PD[1]. 2. Mechanism of action: Pramipexole (SND-919) exerts its therapeutic effect by activating postsynaptic D2/D3 receptors in the striatum, compensating for the loss of endogenous dopamine in PD. It also promotes neuronal survival through two pathways: (1) upregulating BDNF and activating the mTOR pathway, enhancing the structural plasticity of dopaminergic neurons; (2) stabilizing mitochondrial membrane potential and inhibiting caspase-3 activation to reduce apoptosis [1, 3, 5]
3. Neuroprotective potential: Preclinical data show that pramipexole (SND-919) can protect dopaminergic neurons from levodopa-induced oxidative stress (by reducing ROS and LDH release) and ischemic damage (by inhibiting mitochondrial dysfunction and apoptosis), suggesting its potential to delay the progression of Parkinson's disease or treat ischemic stroke [4, 5]
4. Pharmacodynamic characteristics: Compared with other dopamine agonists (e.g., ropinirole), pramipexole (SND-919) has higher selectivity for D3 receptors (Ki D3 < Ki D2), which may contribute to its better tolerability in patients with Parkinson's disease (lower incidence of motor dysfunction) [1, 3].

C10H17N3S

211.33

211.114

C, 56.84; H, 8.11; N, 19.88; S, 15.17

104632-26-0

Pramipexole dihydrochloride; 104632-25-9; Dexpramipexole dihydrochloride; 104632-27-1; Pramipexole dihydrochloride hydrate; 191217-81-9; Dexpramipexole;104632-28-2; Pramipexole-d5; 1217975-28-4

119570

White to off-white solid powder

1.2±0.1 g/cm3

378.0±42.0 °C at 760 mmHg

288-290°C

182.4±27.9 °C

0.0±0.9 mmHg at 25°C

1.583

1.42

2

4

3

14

188

1

S1C(N([H])[H])=NC2=C1C([H])([H])[C@]([H])(C([H])([H])C2([H])[H])N([H])C([H])([H])C([H])([H])C([H])([H])[H]

FASDKYOPVNHBLU-ZETCQYMHSA-N

InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1

(6S)-6-N-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine

2934.99.03.00

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)

Solubility in Formulation 1: 10 mg/mL (47.32 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.83 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.83 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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