5-HT2A ( Ki = 0.17 nM ); α2c-adrenergic receptor ( Ki = 1.3 nM ); α2c-adrenergic receptor ( Ki = 1.3 nM ); D2 receptor ( Ki = 3.57 nM ); D3 receptor ( Ki = 3.6 nM ); D2L Receptor ( Ki = 4.16 nM )

In vitro activity: Risperidone binds to serotonin (5HT) and dopamine (DA) receptors, especially those found in the neurons of the limbic and striatal regions. Risperidone dramatically alters the amount of brain nerve growth factor (NGF), indicating that it has an impact on endogenous growth factor turnover. Risperidone either increases or decreases TrkB receptors in specific brain structures and significantly reduces BDNF concentrations in the hippocampus, occipital cortex, and frontal cortex.[1] In rat forebrain regions, risperidone dramatically increases D(2) binding by 34% in the medial prefrontal cortex. In rat forebrain regions, risperidone causes an even higher up-regulation of D(4) receptors in CPu (37%), NAc (32%), and HIP (37%).[2] Risperidone dramatically reduces activated microglia's ability to produce proinflammatory cytokines and NO.[3] Risperidone (1-50 mM) increases the intracellular accumulation of Rh123 in Caco-2 cells by IC(50) = 5.87 mM, which is the inhibitory effect of P-gp activity. [4]

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Microglia has recently been regarded to be a mediator of neuroinflammation via the release of proinflammatory cytokines, nitric oxide (NO) and reactive oxygen species (ROS) in the central nervous system (CNS). Microglia has thus been reported to play an important role in the pathology of neurodegenerative disease, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The pathological mechanisms of schizophrenia remain unclear while some recent neuroimaging studies suggest even schizophrenia may be a kind of neurodegenerative disease. Risperidone has been reported to decrease the reduction of MRI volume during the clinical course of schizophrenia. Many recent studies have demonstrated that immunological mechanisms via such as interferon (IFN)-γ and cytokines might be relevant to the pathophysiology of schizophrenia. In the present study, we thus investigated the effects of risperidone on the generation of nitric oxide, inducible NO synthase (iNOS) expression and inflammatory cytokines: interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α by IFN-γ-activated microglia by using Griess assay, Western blotting and ELISA, respectively. In comparison with haloperidol, risperidone significantly inhibited the production of NO and proinflammatory cytokines by activated microglia. The iNOS levels of risperidone-treated cells were much lower than those of the haloperidol-treated cells. Antipsychotics, especially risperidone may have an anti-inflammatory effect via the inhibition of microglial activation, which is not only directly toxic to neurons but also has an inhibitory effect on neurogenesis and oligodendrogenesis, both of which have been reported to play a crucial role in the pathology of schizophrenia.[3]

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Risperidone (RSP) and its major active metabolite, 9-hydroxy-risperidone (paliperidone, PALI), are substrates of the drug transporter P-glycoprotein (P-gp). The goal of this study was to examine the in vitro effects of RSP and PALI on P-gp-mediated transport. The intracellular accumulation of rhodamine123 (Rh123) and doxorubicin (DOX) were examined in LLC-PK1/MDR1 cells to evaluate P-gp inhibition by RSP and PALI. Both compounds significantly increased the intracellular accumulation of Rh123 and DOX in a concentration-dependent manner. The IC50 values of RSP for inhibiting P-gp-mediated transport of Rh123 and DOX were 63.26 and 15.78 μM, respectively, whereas the IC50 values of PALI were >100 μM, indicating that PALI is a less potent P-gp inhibitor. Caco-2 and primary cultured rat brain microvessel endothelial cells (RBMECs) were utilized to investigate the possible influence of RSP on intestinal absorption and blood–brain barrier (BBB) transport of coadministered drugs that are P-gp substrates. RSP, 1–50 μM, significantly enhanced the intracellular accumulation of Rh123 in Caco-2 cells by inhibiting P-gp activity with an IC50 value of 5.87 μM. Following exposure to 10 μM RSP, the apparent permeability coefficient of Rh123 across Caco-2 and RBMECs monolayers was increased to 2.02 and 2.63-fold in the apical to basolateral direction, but decreased to 0.37 and 0.21-fold in the basolateral to apical direction, respectively. These data suggest that RSP and PALI, to a lesser extent, have a potential to influence the pharmacokinetics and hence the pharmacodynamics of coadministered drugs via inhibition of P-gp-mediated transport. However, no human data exist that address this issue. In particular, RSP may interact with its own active metabolite PALI by promoting its brain concentration through inhibiting P-gp-mediated efflux of PALI across endothelial cells of the BBB [4].

Risperidone does not significantly impact leptin levels, glucose tolerance, bodyweight gain (BWG), or food intake (FI), despite the fact that prolactin and corticosterone are markedly increased in male rats. In female rats, risperidone dramatically raises BWG and FI.[5] In white adipose tissue (WAT), risperidone (0.05 mg/kg) increases food intake and leptin gene expression; however, it has no effect on the rate of bodyweight gain in rats. In rats, risperidone (0.5 mg/kg) reduces bodyweight gain and increases serum prolactin concentrations and Ucp1 gene expression in BAT.[6]

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The antipsychotics haloperidol and Risperidone are widely used in the therapy of schizophrenia. The former drug mainly acts on the dopamine (DA) D(2) receptor whereas risperidone binds to both DA and serotonin (5HT) receptors, particularly in the neurons of striatal and limbic structures. Recent evidence suggests that neurotrophins might also be involved in antipsychotic action in the central nervous system (CNS). We have previously reported that haloperidol and risperidone significantly affect brain nerve growth factor (NGF) level suggesting that these drugs influence the turnover of endogenous growth factors. Brain-derived neurotrophic factor (BDNF) supports survival and differentiation of developing and mature brain DA neurons. We hypothesized that treatments with haloperidol or risperidone will affect synthesis/release of brain BDNF and tested this hypothesis by measuring BDNF and TrkB in rat brain regions after a 29-day-treatment with haloperidol or risperidone added to chow. Drug treatments had no effects on weight of brain regions. Chronic administration of these drugs, however, altered BDNF synthesis or release and expression of TrkB-immunoreactivity within the brain. Both haloperidol and risperidone significantly decreased BDNF concentrations in frontal cortex, occipital cortex and hippocampus and decreased or increased TrkB receptors in selected brain structures. Because BDNF can act on a variety of CNS neurons, it is reasonable to hypothesize that alteration of brain level of this neurotrophin could constitute one of the mechanisms of action of antipsychotic drugs. These observations also support the possibility that neurotrophic factors play a role in altered brain function in schizophrenic disorders. [1]

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Changes in members of the dopamine (DA) D(1)-like (D(1), D(5)) and D(2)-like (D(2), D(3), D(4)) receptor families in rat forebrain regions were compared by quantitative in vitro receptor autoradiography after prolonged treatment (28 days) with the atypical antipsychotics olanzapine, Risperidone, and quetiapine. Olanzapine and risperidone, but not quetiapine, significantly increased D(2) binding in medial prefrontal cortex (MPC; 67% and 34%), caudate-putamen (CPu; average 42%, 25%), nucleus accumbens (NAc; 37%, 28%), and hippocampus (HIP; 53%, 30%). Olanzapine and risperidone, but not quetiapine, produced even greater up-regulation of D(4) receptors in CPu (61%, 37%), NAc (65%, 32%), and HIP (61%, 37%). D(1)-like and D(3) receptors in all regions were unaltered by any treatment, suggesting their minimal role in mediating actions of these antipsychotics. The findings support the hypothesis that antipsychotic effects of olanzapine and risperidone are partly mediated by D(2) receptors in MPC, NAc, or HIP, and perhaps D(4) receptors in CPu, NAc, or HIP, but not in cerebral cortex. Selective up-regulation of D(2) receptors by olanzapine and risperidone in CPu may reflect their ability to induce some extrapyramidal effects. Inability of quetiapine to alter DA receptors suggests that nondopaminergic mechanisms contribute to its antipsychotic effects. [2]

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Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of Risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet. [5]

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1. Risperidone is an atypical antipsychotic drug that possesses 5-hydroxytryptamine 5-HT2 receptor antagonism combined with milder dopamine D2 receptor antagonism. 2. Excessive bodyweight gain is one of the side-effects of antipsychotics. Risperidone treatment causes a greater increase in the body mass of patients than treatment with conventional antipsychotics, such as haloperidol. Therefore, the present study was undertaken in order to address the aetiology of the risperidone-induced bodyweight change in rats by examining the expression of leptin, an appetite-regulating hormone produced in white adipose tissue (WAT), and uncoupling protein (UCP)-1, a substance promoting energy expenditure in the brown adipose tissues (BAT). 3. Eight-week-old male rats were injected subcutaneously with risperidone (0.005, 0.05 or 0.5 mg/kg) twice daily for 21 days. Both bodyweight and food intake were monitored daily. On day 21, rats were decapitated and their serum leptin and prolactin concentrations were measured. Expression levels of leptin, Ucp1 and beta3-adrenoceptor (beta3-AR) genes in WAT and BAT were quantified using real-time polymerase chain reaction amplification. 4. Injection of 0.005 mg/kg risperidone into rats increased food intake and the rate of bodyweight gain, as well as the augmentation of leptin gene expression in WAT. Injection of 0.05 mg/kg risperidone increased food intake and leptin gene expression in WAT, but the rate of bodyweight gain was not affected. Injection of 0.5 mg/kg risperidone caused a reduction in bodyweight gain, as well as enhanced Ucp1 gene expression in BAT and serum prolactin concentrations. The serum leptin concentration and beta3-AR gene expression in WAT and BAT were not affected by injection of 0.5 mg/kg risperidone. 5. Although the changes in food intake observed in risperidone-injected rats were rationalized neither by serum leptin nor prolactin concentrations, the reduction in the rate of bodyweight gain following injection of 0.5 mg/kg can be explained, in part, by increased energy expenditure, as revealed by the remarkable increase in the UCP-1 mRNA expression level in BAT. The role of leptin in risperidone-induced alterations in bodyweight gain remain to be clarified [6].

Cell viability [3]
Cell viability was determined by colorimetric measurements of the reduction product of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetra-zolium bromide (MTT). After treatment with or without haloperidol and Risperidone, the original medium was removed from the 96-well plates, and the cells were incubated for 2 h at 37 °C in the presence of phenol red free minimum essential medium containing 0.5 mg/mL MTT. A 100 mL aliquot of acid–isopropanol (0.04 mol/L hydrochloric acid) was then added to each well, and the plates were incubated at 37 °C overnight to dissolve the formazan that had formed in the wells. MTT is reduced to formazan in the mitochondria of living cells. Reduced MTT was measured by means of a plate reader at a wavelength of 570 nm.

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Nitrite production assessment [3]
The accumulation of NO2−, a stable end-product, extensively used as an indicator of NO production by cultured cells, was assayed using the Griess reaction. The 6–3 cells were plated on 96-well tissue culture plates at 1 × 105 per 200 μl per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C. After 48 h, the cell-free supernatants were mixed with equal amounts of Griess reagent. Samples were incubated at room temperature for 15 min and subsequently absorbance was read at 540 nm using a plate reader.

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Western blotting for the detection of inducible NO synthase (iNOS) [3]
The 6–3 microglial cells were plated on 35 mm tissue culture dishes at a density of 1.8 × 106 cells per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C for 12 h. Afterwards, the cells were washed with PBS (pH 7.4) and lysed with sodium dodecylsulfate (SDS)-containing sample buffer. Proteins were separated in a 7.5% SDS–polyacrylamide gel and transferred onto a nitrocellulose membrane. The membrane was incubated with 5% non-fat dry milk to block non-specific binding. Subsequently, the membrane was incubated with iNOS antibodies and β-actin antibodies. The expression of iNOS and β-actin were detected using enhanced chemiluminescence system. The band intensity was quantified with a densitometric scanner. The experiments were performed three times independently.

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Cytokine release assessment [3]
The 6–3 cells were plated on 96-well tissue culture plates at 1 × 105 per 200 μl per well and then were pre-incubated in the presence or absence of haloperidol or Risperidone for 12 h and then incubated in the presence or absence of 50 U/ml IFN-γ at 37 °C. After 48 h, the collected media were assayed for cytokine (IL-1β, IL-6 and TNF-α) accumulation. Cytokines released into the culture medium were measured using mouse IL-1β, IL-6 and TNF-α enzyme-linked immunosorbent assay (ELISA) kits based on the quantitative “sandwich” enzyme immunosorbent technique. The assays were carried out according to the manufacturer's protocol. The sensitivity of this assay was 4 pg/ml.

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Intracellular Rh123 and DOX Accumulation Studies [4]
Intracellular accumulation of P-gp substrates Rh123 and DOX were measured to evaluate the P-gp activity in LLC-PK1/MDR1 and Caco-2 cells whereas LLC-PK1 was included as a negative control (van der Sandt et al, 2000). After reaching confluence, cells were preincubated at 37°C for 30 min with transport buffer (serum-free DMEM containing 25 mM N-2-hydroxyl piperazine-N′-2-ehane sulfonic acid, pH 7.4). Vehicle control (0.5% dimethylsulfoxide (DMSO)), specific concentrations of RSP/Risperidone, PALI, or PSC833 were added, then 5 μM of Rh123 or 10 μM of DOX were added for an additional 60 min incubation. After incubation, the solutions were discarded, and the cells were washed three times with ice-cold DPBS and solubilized with 1% Triton X-100. The fluorescence of Rh123 and DOX were measured by high-performance liquid chromatography (HPLC) assay. The concentrations were determined from the fluorescence value through the construction of Rh123 and DOX standard curves. The amount of Rh123 or DOX in each sample was standardized with the protein content as determined by the Lowry assay.

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Rh123 Transport Studies [4]
When RBMECs or Caco-2 cells reached confluence, the integrity of monolayers was checked by both TEER value and the transport rate of fluorescein, a recognized paracellular transport marker (van Bree et al, 1988). The qualified monolayers were rinsed two times with DPBS and preincubated with transport buffer at 37°C for 30 min. In all, 0.5% DMSO, RSP/Risperidone, or PSC833 was loaded at both sides of the monolayers, then Rh123 (5 μM) was added into the basolateral side for the basolateral to apical (B–A) transport study or apical side for the apical to basolateral (A–B) transport study. At designated times, 150 μl samples were taken from the receiver compartment, and the same volume of receiver compartment solution was replaced immediately after each sampling. Concentrations of Rh123 were determined by HPLC. Apparent permeability coefficients, Papp (cm/s) were calculated according to the following equation:

A total of 211 Long-Evans rats are utilized, comprising 56 females and 155 males. Three groups of approximately equal numbers of rats are injected with either 1.0 mg/kg of risperidone, 3.0 mg/kg of risperidone, or the vehicle used to administer the Risperidone solution as a control within each study. Twenty-six male rats (n = 9 in the vehicle and 3.0 mg/kg Risperidone groups; n = 8 in the 1.0 mg/kg Risperidone group) are used in the first experiment. They are tested for locomotor activity for 20 minutes every day starting on postnatal day 49 and continuing every day until postnatal day 53. The long-term effects of early-life Risperidone treatment on locomotion were examined in a follow-up study. In a third experiment, the effects of sex on early-life Risperidone's locomotor effects in young adult rats are investigated. Sixty male (n = 20 per treatment group) and fifty-six female (n = 19 rats in the vehicle and 3.0 mg/kg dose group, n = 18 in the 1.0 mg/kg dose group) rats are treated in this experiment. In a fourth experiment, rats given risperidone early in life were evaluated for reversal learning during adulthood. Treatment is given to 42 male rats (n=14 per treatment group).

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Drug treatment [5]
Racemic SUL and RisperidoneRIS were dissolved in 0.1 N HCl and tartaric acid respectively, and pH was adjusted to 7.0. Drugs were administered subcutaneously in a volume of 0.1 cc/100 g.
Blood sampling and oral glucose tolerance test [5]
General anesthesia was achieved by intramuscular administration of a solution made of Ketamine HCl (50 mg/ml), Xylazine HCl (5 mg/kg) and Acepromazine (1 mg/kg). The total volume was 1 ml/kg of BW. A catheter was placed in the tail dorsal artery and was filled with heparinized (2 U/ml) physiological saline at 12:00. The oral glucose tolerance test (glucose, 1 g/kg per gavage) was conducted in a counterbalanced order 36 h after surgery. Blood samples (0.1 cc) were removed before and after the glucose administration (at 0, 30, 60, 90 and 120 min; total 0.6 cc of blood) while the animal was gently placed in a plastic rodent restrainer. The catheter was immediately withdrawn at the end of the glucose tolerance test, and 2 days later the rats were decapitated after 6 hours of fasting. Trunk blood was collected for hormonal determination. For this purpose all animals were decapitated in a counterbalanced sequence between 17:00 and 19:00 h. In order to minimize the effects of stress on hormone levels, less than 1 minute elapsed between handling the animals and decapitation. Bodies were processed for body composition analysis (see below).

Experiment 1: Effects of Risperidone on BW and FI in female or male rats [5]
For each gender, 32 animals were randomly assigned to 4 groups of 8 subjects each, which received one of the following treatments: vehicle (0.1 cc/kg), Risperidone/RIS 0.125, 0.25 or 0.5 mg/kg for 16 days. These doses of RIS are known to induce little impairment in motor behavior in rats. Measurement of BWG and FI was conducted as stated above. Since no additional studies were carried out in males, an oral glucose tolerance test was conducted in the rats treated with VEH and RIS 0.5 mg/kg at day 14. Serum glucose and insulin levels were assessed in all blood samples. Leptin, corticosterone and prolactin levels were measured in blood samples collected immediately after decapitation of the animals at the end of the experiment.

Experiment 2: Comparison between the effects of Risperidone and sulpiride on BW, FI, glucose tolerance, vaginal cycle, hormones and glucose tolerance in female rats [5]
Twenty-nine female rats were divided into 3 groups that received one of the following treatments for 12 days: 0.9% NaCl, 0.1 cc/kg (n=9), RIS 0.5 mg/kg (n=11) or SUL 20 mg/kg (n=9). This SUL dose has been shown to induce the maximal BWG after prolonged treatment. The intra-arterial catheter was placed on day 9 after onset of drug treatment, and was withdrawn when the glucose test was completed. On day 10 the animals were fasted for 6 hours and then the oral glucose tolerance test was conducted as described in the blood sampling section. Insulin and glucose were assessed in all blood samples. Leptin, corticosterone, prolactin, progesterone and estradiol concentrations were assessed in the basal samples obtained by decapitation on day 12.

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Risperidone was used. Eight-week-old male Sprague-Dawley rats, weighing 285–305 g, were housed individually, maintained on a 12 h light/dark cycle (lights on at 06.00 h) and allowed free access to standard rodent food (CE-2; 14.4 kJ/g, consisting of 12% fat, 29% protein and 59% carbohydrate) and water. Room temperature was maintained at 23 ± 1°C. After habituation for 3 days, rats were divided into four experimental groups. Three groups were injected twice daily (09.00 and 18.00 h) for 21 days by subcutaneous (s.c.) injection into the neck region with Risperidone at concentrations of 0.005, 0.05 or 0.5 mg/kg (n = 5, 6 and 5, respectively), with rats in their home chambers. Another 10 rats received s.c. injection into the neck region of vehicle (0.3% tartaric acid) twice daily at 09.00 and 18.00 h for 21 days. Bodyweight and food intake were recorded daily to the nearest 1.0 g just before the injection at 09.00 h. On day 21, 1 h after the 18.00 h injection, rats were decapitated. Blood samples were obtained from the trunk vessels and the sera were kept at −80°C until hormone assays could be performed. The epididymal WAT and interscapular BAT were rapidly removed and stored at −80°C prior to RNA extraction [6].

Absorption, Distribution and Excretion
Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.
Risperidone is extensively metabolized in the liver. In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives are prolonged compared to young healthy subjects.
The volume of distribution of risperidone is approximately 1 to 2 L/kg.
Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with a creatinine clearance (ClCr) between 15-59 mL/min, in whom clearance is decreased by approximately 60%.
Risperidone is well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.
Risperidone is rapidly distributed. The volume of distribution is 1-2 L/kg. In plasma, risperidone is bound to albumin and a1-acid glycoprotein. The plasma protein binding of risperidone is 90%, and that of its major metabolite, 9-hydroxyrisperidone, is 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites. High therapeutic concentrations of sulfamethazine (100 ug/mL), warfarin (10 ug/mL), and carbamazepine (10 ug/mL) caused only a slight increase in the free fraction of risperidone at 10 ng/mL and 9-hydroxyrisperidone at 50 ng/mL, changes of unknown clinical significance.
Plasma concentrations of risperidone, its major metabolite, 9-hydroxyrisperidone, and risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg twice daily). Following oral administration of solution or tablet, mean peak plasma concentrations of risperidone occurred at about 1 hour. Peak concentrations of 9-hydroxyrisperidone occurred at about 3 hours in extensive metabolizers, and 17 hours in poor metabolizers. Steady-state concentrations of risperidone are reached in 1 day in extensive metabolizers and would be expected to reach steady-state in about 5 days in poor metabolizers. Steady-state concentrations of 9-hydroxyrisperidone are reached in 5-6 days (measured in extensive metabolizers).
Risperidone and 9-hydroxyrisperidone are present in human breast milk.
For more Absorption, Distribution and Excretion (Complete) data for RISPERIDONE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone (i.e. [paliperidone]), which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.
Risperidone is extensively metabolized in the liver. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by the enzyme, CYP 2D6. A minor metabolic pathway is through N-dealkylation. The main metabolite, 9-hydroxyrisperidone, has similar pharmacological activity as risperidone. Consequently, the clinical effect of the drug results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP 2D6, also called debrisoquin hydroxylase, is the enzyme responsible for metabolism of many neuroleptics, antidepressants, antiarrhythmics, and other drugs. CYP 2D6 is subject to genetic polymorphism (about 6%-8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP 2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP 2D6 metabolizers convert it much more slowly. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers.
Risperidone has known human metabolites that include 9-Hydroxy-risperidone, Paliperidone, 3-[2-[4-(6-fluoro-2-hydroxy-1,2-benzoxazol-2-ium-3-yl)piperidin-1-yl]ethyl]-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, 3-ethyl-2,9-dimethyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one, and 6-Fluoro-3-(4-piperidinyl)-1,2-benzisoxazole.
Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone, which has approximately the same receptor binding affinity as risperidone. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase. Risperidone also undergoes N-dealkylation to a lesser extent.
Route of Elimination: Risperidone is extensively metabolized in the liver.In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects.
Half Life: 20-24 hours

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Biological Half-Life
3 hours in extensive metabolizers Up to 20 hours in poor metabolizers
The apparent half-life of risperidone plus 9-hydroxyrisperidone following Risperdal Consta administration is 3 to 6 days, and is associated with a monoexponential decline in plasma concentrations. This half-life of 3-6 days is related to the erosion of the microspheres and subsequent absorption of risperidone.
The apparent half-life of risperidone was 3 hours (CV=30%) in extensive metabolizers and 20 hours (CV=40%) in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours (CV=20%) in extensive metabolizers and 30 hours (CV=25%) in poor metabolizers. The pharmacokinetics of risperidone and 9-hydroxyrisperidone combined, after single and multiple doses, were similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.

Toxicity Summary
Blockade of dopaminergic D2 receptors in the limbic system alleviates positive symptoms of schizophrenia such as hallucinations, delusions, and erratic behavior and speech. Blockade of serotonergic 5-HT₂ receptors in the mesocortical tract, causes an excess of dopamine and an increase in dopamine transmission, resulting in an increase in dopamine transmission and an elimination of core negative symptoms. Dopamine receptors in the nigrostriatal pathway are not affected by risperidone and extrapyramidal effects are avoided. Like other 5-HT₂ antagonists, risperidone also binds at alpha(1)-adrenergic receptors and, to a lesser extent, at histamine H1 and alpha(2)-adrenergic receptors.

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Toxicity Data
LD₅₀=82.1mg/kg (orally in mice).

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Interactions
Given the primary CNS effects of risperidone, caution should be used when Risperdal is taken in combination with other centrally-acting drugs and alcohol.
Risperdal may antagonize the effects of levodopa and dopamine agonists.
When Risperdal is co-administered with enzyme inducers (e.g., carbamazepine), the dose of Risperdal should be increased up to double the patient's usual dose. It may be necessary to decrease the Risperdal dose when enzyme inducers such as carbamazepine are discontinued [see Drug Interactions (7.1)]. Similar effect may be expected with co-administration of Risperdal with other enzyme inducers (e.g., phenytoin, rifampin, and phenobarbital).
Chronic administration of clozapine with Risperdal may decrease the clearance of risperidone.
For more Interactions (Complete) data for RISPERIDONE (10 total), please visit the HSDB record page.

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Hepatotoxicity
Liver test abnormalities may occur in up to 30% of patients on long term therapy with risperidone, usually arising within the first 8 weeks of treatment. The ALT elevations are usually mild, transient and may resolve even with continuation of medication. Instances of more marked ALT and alkaline phosphatase elevations, with or without symptoms and with or without jaundice, have also been reported. The onset of injury typically occurs within a few days of starting risperidone and resolves rapidly with stopping. Instances of acute liver injury with jaundice arising several months and even years after starting risperidone have also been reported. The pattern of serum enzyme elevations is typically cholestatic, but cases with hepatocellular and mixed patterns have also been described. Immunoallergic manifestations (rash, fever, eosinophilia) are rare; a case of autoimmune hepatitis apparently triggered by risperidone therapy has been published, but most cases do not have autoimmune features.

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Limited information indicates that maternal risperidone doses of up to 6 mg daily produce low levels in milk. Sedation, failure to thrive, jitteriness, tremors, abnormal muscle movements and respiratory depression have been reported in infants exposed to risperidone in milk. Because there is little published experience with risperidone during breastfeeding and little long-term follow-up data, other agents may be preferred, especially while nursing a newborn or preterm infant. Systematic reviews of second-generation antipsychotics concluded that risperidone seemed to be a second-line agent during breastfeeding because of the limited data available and higher excretion into milk relative to other agents. A safety scoring system finds risperidone to be possible to use cautiously during breastfeeding. Monitor the infant for drowsiness, weight gain, tremors, respiratory rate, abnormal muscle movements, and developmental milestones, especially if other antipsychotics are used concurrently.

◉ Effects in Breastfed Infants
One woman took risperidone 4 mg daily during breastfeeding. Her infant showed no developmental abnormalities on examinations up to 9 months of age. Another mother took risperidone 6 mg daily during breastfeeding. Her infant showed no developmental abnormalities on examinations up to 12 months of age.
Two women taking risperidone 4 mg and 1.5 mg daily breastfed their infants of 3.3 months and 6 weeks of age, respectively, were achieving normal developmental milestones and had no adverse effects reported.
A 1 week postpartum woman was started on risperidone 2 mg daily and increased after 10 days to a dosage of 3 mg daily. She breastfed her infant 6 times daily. The infant was observed for 5 weeks of inpatient therapy and judged normal by a pediatric neurologist. No sedation or other adverse effects were observed in the infant. After 3 months of treatment with risperidone, the mother and infant were judged to be well.
An infant had been exclusively breastfed for 3 months during maternal therapy with risperidone 1 mg daily. A pediatric examination found the infant to have no neurological or physical abnormalities, and appeared to interact appropriately.
In a telephone follow-up study, 124 mothers who took a benzodiazepine while nursing reported whether their infants had any signs of sedation. One mother who was taking 0.75 mg of risperidone daily, flurazepam 15 mg daily, clonazepam 0.25 mg twice daily, and 1 mg of bupropion daily reported sedation in her breastfed infant.
A woman diagnosed with schizophrenia was taking risperidone 1.5 mg daily during late pregnancy and postpartum while nursing (extent not stated) her full-term infant. At 2 weeks postpartum, haloperidol 0.8 mg daily was added because of a recurrence of symptoms. At these dosages, no adverse effects were seen in the infant. However, because of recurring symptoms, the dosage of haloperidol was increased to 1.5 mg daily. Three days later, the infant had excessive sedation, poor feeding, and slowing in motor movements. Pediatric assessment found no medical reason for these effects. Breastfeeding was discontinued and the infant's symptoms resolved completely in 5 days. The infant's symptoms were probably caused by the drug combination.
A prospective cohort study of infants breastfed by mothers in an inpatient mother-baby psychiatric unit in India followed 7 infants who were exposed to risperidone in breastmilk; most received partial supplementation. One infant whose mother was taking risperidone 4 mg and lorazepam 2 mg developed sedation that resolved when lorazepam was discontinued. One infant whose mother received risperidone 4 mg daily, trihexyphenidyl 2 mg daily, and electroconvulsive therapy developed constipation. Infants were followed for 1 to 3 months after discharge. One infant had delayed weight development, one infant had delay in height, one infant mental delay, and a fourth infant had motor and mental delay.
A woman with bipolar disorder was maintained on oral risperidone 2 mg at bedtime, long-acting injectable risperidone 50 mg intramuscular every 2 weeks, oral citalopram 20 mg daily, and oral benztropine 0.5 mg daily. She became pregnant and maintained the same regimen. Her infant was born at 35 weeks gestational age and was breastfed (extent and duration not stated). At 16 months of age, the infant was doing well and met his developmental milestones.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking risperidone was not reported.
A preterm infant weighing 2.75 kg was born at 35 weeks gestation. The infant received bag and mask ventilation for 2 min and was kept on oxygen for the first 18 hours of life due to respiratory distress. The baby began breastfeeding on day 2 of life. On day 12, the mother was started on risperidone 1 mg daily for psychotic episodes. On day 13, the infant developed a respiratory rate of 16/min and no retractions and was placed on CPAP for 12 hours, with gradual weaning thereafter and was placed on formula. On day 15, the mother began breastfeeding again and the respiratory depression recurred. Feeding was changed to breastmilk expressed prior to the daily dose of risperidone and formula for 6 hours after each dose followed by direct breastfeeding. Over the next 2 days no further episodes of respiratory depression occurred. The baby was discharged on day 24, with advice to continue the same feeding pattern. Respiratory depression was probably caused by risperidone in milk.
A woman diagnosed with undifferentiated schizophrenia took risperidone 4 to 5 mg and trihexyphenidyl 2 mg daily throughout 5 pregnancies. She breastfed each infant for 20 to 24 months. No adverse developmental consequences were noted in any of the children. At the time of publication, the oldest three children, aged 26, 23 and 22 years, had completed their education and were employed, while the youngest two were 15 and 19 years old and were doing well academically in their education.

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◉ Effects on Lactation and Breastmilk
Risperidone has caused elevated prolactin serum levels, gynecomastia, and galactorrhea in patients taking the drug. In one case, euprolactinemic gynecomastia and galactorrhea occurred in a 19-year-old man who was also taking fluvoxamine. A meta-analysis of 3 studies found that the risk of gynecomastia with risperidone is 4.3 times greater than that of quetiapine. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who primarily had diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking risperidone was not reported.

◈ What is risperidone?
Risperidone is a medication that has been used to treat mental health conditions such as schizophrenia, bipolar disorder, and depression. It can be taken by mouth or given as an injection. Risperidone belongs to a group of medications called atypical or second-generation antipsychotics. Brand names for risperidone include Risperdal®, Risperdal Consta®, and Perseris®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I take risperidone. Can it make it harder for me to get pregnant?
In some people, risperidone may raise the levels of a hormone called prolactin. High levels of prolactin can stop ovulation (part of the menstrual cycle when an ovary releases an egg). This would make it harder to get pregnant. Your healthcare provider can test your levels of prolactin if there is concern.

◈ Does taking risperidone increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Based on the studies reviewed, risperidone is not expected to increase the chance of miscarriage.

◈ Does taking risperidone increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Based on the studies reviewed, risperidone is not expected to increase the chance of birth defects above the background risk.

◈ Does taking risperidone in pregnancy increase the chance of other pregnancy-related problems?
Based on the studies reviewed, risperidone may cause low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).Risperidone may cause weight gain and problems with blood sugar in a person who is pregnant. This may increase the chance of developing gestational diabetes. More information about gestational diabetes can be found in our fact sheet https://mothertobaby.org/fact-sheets/diabetes-pregnancy/.

◈ I need to take risperidone throughout my entire pregnancy. Will it cause withdrawal symptoms in my baby after birth?
The use of some medications during pregnancy may cause temporary symptoms in newborns soon after birth. These symptoms are sometimes referred to as withdrawal. It is unknown if taking risperidone alone could increase the chance of withdrawal symptoms in a newborn. Similar medications have been associated with a chance for withdrawal, so babies exposed to risperidone near the time of delivery should be watched for stiff or floppy muscles, drowsiness, agitation, tremors, trouble breathing, and problems with feeding. In most cases, symptoms would be expected to go away in a few days without any long-term health effects. It is important that your healthcare providers know you are taking risperidone so that if symptoms occur your baby can get the care that is best for them.

◈ Does taking risperidone in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if risperidone can cause behavior or learning issues for the child.

◈ Breastfeeding while taking risperidone:
Information on the use of risperidone during breastfeeding is limited. When taken in doses of up to 6 mg a day risperidone was found in breastmilk in small amounts. Side effects were not reported in a small number of breastfed infants who were exposed to risperidone only (in doses of up to 6 mg a day). If you take risperidone and other medications, there may be a higher chance for side effects in the baby. If you suspect the baby has any symptoms (sleepiness, poor feeding, crankiness, or unusual movements) contact the child’s healthcare provider.The product label for risperidone recommends that people who are breastfeeding not use this medication. But the benefit of using risperidone may outweigh the possible risks. Your healthcare providers can talk with you about using risperidone and what treatment is best for you. Be sure to talk to your healthcare provider about all of your breastfeeding questions.

◈ If a male takes risperidone, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Using risperidone may raise a person’s levels of the hormone prolactin, which may affect fertility. Studies have not been done to see if risperidone could increase the chance of birth defects above the background risks. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

[1]. J Neurosci Res. 2000 Jun 15;60(6):783-94.

[2]. J Pharmacol Exp Ther. 2001 May;297(2):711-7.

[3]. Schizophr Res,?007, 92(1-3), 108-115.

[4]. Neuropsychopharmacology. 2007 Apr;32(4):757-64.

[5]. Brain Res. 2002 Dec 6;957(1):144-51.

[6]. Clin Exp Pharmacol Physiol. 2002 Nov;29(11):980-9.

Therapeutic Uses
Antipsychotic Agents; Dopamine Antagonists; Serotonin Antagonists
Risperdal (risperidone) is indicated for the treatment of schizophrenia. Efficacy was established in 4 short-term trials in adults, 2 short-term trials in adolescents (ages 13 to 17 years), and one long-term maintenance trial in adults /Included in US product label/
Risperdal adjunctive therapy with lithium or valproate is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in one short-term trial in adults. /Included in US product label/
Risperdal is indicated for the treatment of irritability associated with autistic disorder, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods. Efficacy was established in 3 short-term trials in children and adolescents (ages 5 to 17 years). /Included in US product label/
Risperdal is indicated for the treatment of acute manic or mixed episodes associated with Bipolar I Disorder. Efficacy was established in 2 short-term trials in adults and one short-term trial in children and adolescents (ages 10 to 17 years). /Included in US product label/

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Drug Warnings
/BOXED WARNING/ WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperdal (risperidone) is not approved for the treatment of patients with dementia-related psychosis.
Like other antipsychotic agents (e.g., phenothiazines), risperidone has been associated with tardive dyskinesias. Although it has been suggested that atypical antipsychotics appear to have a lower risk of tardive dyskinesia, whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is as yet unknown. In one open-label study, an annual incidence of tardive dyskinesia of 0.3% was reported in patients with schizophrenia who received approximately 8-9 mg of oral risperidone daily for at least 1 year. The prevalence of this syndrome appears to be highest among geriatric patients (particularly females). The risk of developing tardive dyskinesia and the likelihood that it will become irreversible also appear to increase with the duration of therapy and cumulative dose of antipsychotic agents administered; however, the syndrome may occur, although much less frequently, after relatively short periods of treatment with low dosages.
Neuroleptic malignant syndrome (NMS), a potentially fatal symptom complex, has been reported in patients receiving antipsychotic agents. NMS requires immediate discontinuance of the drug and intensive symptomatic and supportive care.
Dose-related somnolence was a commonly reported adverse effect associated with risperidone treatment. Approximately 8% of adult patients with schizophrenia receiving 16 mg of oral risperidone daily and 1% of patients receiving placebo reported somnolence in studies utilizing direct questioning or a checklist to detect adverse events, respectively.
For more Drug Warnings (Complete) data for RISPERIDONE (41 total), please visit the HSDB record page.

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Pharmacodynamics
The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders. Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 receptors.

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Antipsychotics have been regarded to effect mainly neurons or neural networks including the synapse network for a long period of time. However, the present study has demonstrated that antipsychotics, especially risperidone, have an anti-inflammatory effect via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on schizophrenic patients by reducing microglial inflammatory reactions, which may inhibit the process of neurogenesis and oligodendrogenesis. These results might shed some new light on the therapeutic strategies for the treatment of schizophrenia. Agents that can inhibit microglial activation may also be useful for the treatment of schizophrenia. For further studies, the molecular mechanism of the inhibitory effect of Risperidone on microglial activation should be clarified in detail while in vivo studies to confirm the present results should also be performed.[3]

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The mechanistic basis of P-gp transport and inhibition has been intensively studied for many years. Several hypotheses have been developed in an effort to explain the molecular mechanism of interaction of P-gp and its substrates or inhibitors. However, owing to multiple drug binding sites on P-gp, the development of a universally accepted model for reconciling the data from various laboratories remains a challenge. It has been demonstrated that there is a minimum of four drug binding sites on P-gp. These sites can be divided into two categories: transport sites, at which translocation of drug across the cellular membrane can occur, and regulatory sites, which modify P-gp function (Martin et al, 2000). In addition, some agents can inhibit P-gp activity by decreasing intracellular ATP supply and inhibiting P-gp ATPase activity (Batrakova et al, 2001). Considering the fact that both Risperidone/RSP and PALI appear to be P-gp substrates as well as inhibitors, competition with other substrates for binding to P-gp is a possible mechanism of their P-gp inhibition. However, other mechanisms cannot be excluded and further studies are needed to elucidate the molecular basis of RSP and PALI interactions with P-gp.[4]

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A final answer regarding an explanation for the alteration in food intake of Risperidone-injected rats was not obtained in the present study from the evidence involving dopamine and/or 5-HT receptor antagonism. However, the reduction in bodyweight gain in risperidone (0.5 mg/kg)-injected rats may be explained, in part, by increased energy expenditure, as revealed by the remarkable increase in UCP-1 mRNA expression in BAT. In humans, BAT is found in the newborn, but it becomes less abundant in adults, in whom the role of BAT is minor.73 This may partially explain the difference in the effect of risperidone on bodyweight gain between rodents and humans. In the present study, we have demonstrated, for the first time, that risperidone injection in rats induced leptin mRNA expression in WAT and UCP-1 mRNA expression in BAT. However, we were not able to provide a rational explanation for these elevated expressions. Thus, our next task is to define the basis for this risperidone-induced increase in mRNA expression levels of these genes in the adipose tissues.[6]

C23H27FN4O2

410.48

410.211

C, 67.30; H, 6.63; F, 4.63; N, 13.65; O, 7.80

106266-06-2

Risperidone-d4; 1020719-76-9; Risperidone hydrochloride; 666179-74-4; Risperidone mesylate; 666179-96-0

5073

White to off-white solid powder

1.4±0.1 g/cm3

572.4±60.0 °C at 760 mmHg

170°C

300.0±32.9 °C

0.0±1.6 mmHg at 25°C

1.677

2.88

0

6

4

30

731

0

FC1C([H])=C([H])C2=C(C=1[H])ON=C2C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C2=C(C([H])([H])[H])N=C3C([H])([H])C([H])([H])C([H])([H])C([H])([H])N3C2=O)C([H])([H])C1([H])[H]

RAPZEAPATHNIPO-UHFFFAOYSA-N

InChI=1S/C23H27FN4O2/c1-15-18(23(29)28-10-3-2-4-21(28)25-15)9-13-27-11-7-16(8-12-27)22-19-6-5-17(24)14-20(19)30-26-22/h5-6,14,16H,2-4,7-13H2,1H

3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

Solubility in Formulation 1: ≥ 1 mg/mL (2.44 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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 2: ≥ 1 mg/mL (2.44 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 10.0 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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Solubility in Formulation 3: ≥ 1 mg/mL (2.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 10.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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