Rat 5-HT_1A Receptor ( Ki = 3.4 nM ); human 5-HT_1A Receptor ( Ki = 2.5 nM ); Rat D₂ Receptor ( Ki = 4.8 nM ); Rat 5-HT_2A ( Ki = 0.42 nM )

Ziprasidone (oral gavage; 20 mg/kg; once daily; 7 weeks) causes reduced levels of physical activity, weight loss, high resting energy expenditure, and an increased ability to produce heat when exposed to cold[3].

Cell Line: HEK-293 cells
Concentration: 0-500 nM
Incubation Time: 150 seconds
Result: Blocked wild-type hERG current in a voltage- and concentration-dependent manner (IC50 = 120 nm).

Eight-week-old female Sprague-Dawley rats weighing 200 to 250 g
20 mg/kg
Oral gavage; 20 mg/kg; once daily; 7 weeks

Absorption, Distribution and Excretion
The oral bioavailability of ziprasidone when taken on an empty stomach is 60%, but can reach 100% when taken with a meal containing at least 500 kcal. Differences in bioavailability are not significantly related to the fat content of the food, but appear to be related to the volume of the meal, as the longer ziprasidone remains in the stomach, the higher the absorption rate. After oral administration, ziprasidone is extensively metabolized, with only a small amount excreted unchanged in urine (<1%) or feces (<4%). The mean apparent volume of distribution of ziprasidone is 1.5 L/kg. The mean apparent systemic clearance is 7.5 mL/min/kg. After oral administration, ziprasidone is well absorbed, reaching peak plasma concentrations in 6 to 8 hours. In the fed state, the absolute bioavailability of a 20 mg dose is approximately 60%. Food can increase the absorption rate of ziprasidone by up to two times. The bioavailability of ziprasidone administered intramuscularly is 100%. Following a single intramuscular injection, peak serum concentrations typically occur approximately 60 minutes or earlier… Steady-state plasma concentrations are reached within 1 to 3 days after administration. The mean apparent systemic clearance is 7.5 mL/min/kg. The mean apparent volume of distribution for ziprasidone is 1.5 L/kg. It binds to over 99% of plasma proteins, primarily albumin and α1-acid glycoprotein. For more complete data on absorption, distribution, and excretion of ziprasidone (11 in total), please visit the HSDB record page. Metabolism/Metabolites Ziprasidone is primarily metabolized in the liver, with less than 5% excreted unchanged in the urine. The primary reduction pathway is catalyzed by aldehyde oxidase, while two less significant oxidation pathways are catalyzed by CYP3A4. Since only one-third of antipsychotic drugs are metabolized via the CYP3A4 system, ziprasidone is unlikely to interact with other drugs metabolized by CYP3A4. Twelve ziprasidone metabolites have been identified (abbreviations in italics): ziprasidone sulfoxide, ziprasidone sulfone, (6-chloro-2-oxo-2,3-dihydro-1H-indol-5-yl)acetic acid (OX-COOH), OX-COOH glucuronide, 3-(piperazin-1-yl)-1,2-benzisothiazole (BITP), BITP sulfoxide, BITP sulfone, BITP sulfone lactam, S-methyl-dihydro-ziprasidone, S-methyl-dihydro-ziprasidone sulfoxide, 6-chloro-5-(2-piperazin-1-yl-ethyl)-1,3-dihydro-indol-2-one (OX-P), and dihydro-ziprasidone sulfone. Depending on the number of metabolites, ziprasidone can be metabolized via multiple pathways. Ziprasidone is sequentially oxidized to ziprasidone sulfoxide and ziprasidone sulfone, while oxidative N-dealkylation of ziprasidone yields OX-COOH and BITP. OX-COOH undergoes phase II metabolism to produce a glucuronidated metabolite, while BITP is sequentially oxidized to BITP sulfoxide and BITP sulfone, ultimately forming BITP sulfone lactam. Ziprasidone can also undergo reductive cleavage and methylation to produce S-methyldihydroziprasidone, which is further oxidized to S-methyldihydroziprasidone sulfoxide. Finally, ziprasidone undergoes dearylation to produce OX-P, which, after hydration and oxidation, is ultimately converted to dihydroziprasidone sulfone. Although CYP3A4 and aldehyde oxidase are the main enzymes involved in ziprasidone metabolism, the metabolic pathways associated with each enzyme are not yet fully understood. Ziprasidone is primarily metabolized extensively in the liver via aldehyde oxidase reduction, with very small amounts of the unchanged drug excreted in urine or feces. Approximately one-third of ziprasidone metabolic clearance is mediated by cytochrome P-450 (CYP) 3A4 isoenzymes. Ziprasidone is primarily cleared via three metabolic pathways, producing four major circulating metabolites: benzisothiazolium (BITP) sulfoxide, BITP sulfone, ziprasidone sulfoxide, and S-methyldihydroziprasidone. In vitro studies using human liver subcellular fractions indicate that the formation of S-methyldihydroziprasidone involves two steps. Data suggest that the reduction reaction is mediated by aldehyde oxidase, followed by methylation mediated by thiol methyltransferase. In vitro studies using human liver microsomes and recombinant enzymes show that CYP3A4 is the major CYP enzyme in the oxidative metabolism of ziprasidone. The contribution of CYP1A2 may be smaller. Based on the abundance of excreted metabolites in vivo, less than one-third of ziprasidone metabolic clearance is mediated by cytochrome P450-catalyzed oxidation, while approximately two-thirds is mediated by the reduction reaction of aldehyde oxidase. Currently, there are no known clinically significant aldehyde oxidase inhibitors or inducers. This study investigated the metabolism and excretion of ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-yl]ethyl]-6-++chloroindoline-2-one hydrochloride hydrate) in Long Evans rats following a single oral administration of a mixture of 14C and 3H-labeled ziprasidone. …Ziprasidone is extensively metabolized in rats, with only a small amount excreted unchanged. A total of 12 metabolites were identified…The structures of 8 metabolites were definitively confirmed by co-elution with synthetic standards using high-performance liquid chromatography (HPLC), and the remaining 4 metabolites were partially identified. Excretion of metabolites in the urine of Long Evans rats showed sex differences. The major metabolic pathway in male rats involved N-dealkylation. The major metabolite in female rats was due to the oxidation of the benzisothiazolium ring. Based on the structures of these metabolites, we identified four major metabolic pathways and two minor metabolic pathways for ziprasidone. The major metabolic pathways include: 1) N-dealkylation of the ethyl side chain on the piperazine nitrogen atom; 2) oxidation of the sulfur atom to generate sulfoxides and sulfones; 3) oxidation of the benzisothiazolium moiety (excluding the sulfur atom); and 4) C=N bond hydration followed by oxidation of the sulfur atom on the benzisothiazolium moiety. The minor metabolic pathways include N-oxidation of the piperazine ring and hydrolysis of the indoleone moiety. Known metabolites of ziprasidone include 6-chloro-5-ethyl-1,3-dihydroindole-2-one, 3-(1-piperazinyl)-1,2-benzisisothiazolium, and ziprasidone sulfoxides. The half-life of ziprasidone is 6–7 hours. Ziprasidone is primarily eliminated via hepatic metabolism, and its mean terminal half-life is approximately 7 hours within the recommended clinical dose range. The mean t(1/2)z times for young men, young women, older men, and older women were 3.1, 4.1, 5.7, and 5.3 hours, respectively.

Toxicity Summary
Indications and Uses: Ziprasidone is indicated for the treatment of schizophrenia. Ziprasidone can be used as monotherapy for the acute phase of manic or mixed episodes in bipolar I disorder. Ziprasidone can be used as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Human Exposure and Toxicity: In patients who received the maximum confirmed dose (3240 mg), the only reported symptoms were mild sedation, dysarthria, and transient hypertension (200/95). In post-marketing use, reported adverse events associated with ziprasidone overdose typically include extrapyramidal symptoms, somnolence, tremor, and anxiety. Previous reports of ziprasidone overdose in children have described a syndrome of sedation, tachycardia, hypotonia, and coma. QTc prolongation and hypotension have been confirmed in cases of ziprasidone overdose in children, but seizures have not been reported. One case of ziprasidone poisoning with pupillary constriction and unresponsiveness to naloxone has been reported. This phenomenon has been previously reported in overdose of similar atypical antipsychotics like olanzapine. The mechanism of pupillary constriction caused by atypical antipsychotic overdose is unclear, but it may be related to interference with the central nervous system innervation of the pupil. The risk of death appears to be higher in Alzheimer's disease-related psychosis patients receiving atypical antipsychotic treatment than in those receiving placebo. One study showed that oral ziprasidone prolongs the QT interval on electrocardiogram by an average of 9-14 milliseconds, higher than in patients taking risperidone, olanzapine, quetiapine, or haloperidol, but shorter by about 14 milliseconds than in patients taking thioridazine. A pediatric patient fell into a coma due to an overdose of ziprasidone; quantitative serum drug concentration testing showed pupillary constriction, indicating that even a single tablet of ziprasidone can cause severe altered mental status and respiratory depression in children. In vitro human lymphocyte chromosome aberration assays also yielded positive results. Psychiatric patients receiving atypical antipsychotic treatment should be closely monitored for rhabdomyolysis during correction of hyponatremia to allow for timely treatment and reduce complications. Animal studies: Lifetime carcinogenicity studies of ziprasidone have been conducted in rats and mice. In a 24-month study, rats were given 2, 6, or 12 mg/kg ziprasidone daily, and mice were given 50, 100, or 200 mg/kg ziprasidone daily (equivalent to 0.1 to 0.6 times and 1 to 5 times the maximum recommended human dose [MRHD] of 200 mg/day, respectively, based on body surface area). In the rat study, no increase in tumor incidence was observed compared to the control group. Tumor incidence was also not higher in male mice than in the control group. In female mice, the incidence of pituitary adenomas and carcinomas, as well as mammary adenocarcinomas, increased in a dose-dependent manner at all tested doses (50 to 200 mg/kg/day, or 1 to 5 times the MRHD based on body surface area). Proliferative changes in the pituitary and mammary glands in rodents following long-term use of other antipsychotic drugs are thought to be prolactin-mediated. A one-month dietary study found elevated serum prolactin levels in female mice (but not male mice) at doses of 100 and 200 mg/kg/day (or, on a mg/m² basis, 2.5 and 5 times the maximum recommended human dose, respectively). A five-week dietary study at the doses used in the carcinogenicity studies showed that ziprasidone had no effect on serum prolactin levels in rats. Ziprasidone did not cause significant weight gain in weeks 1–3, but a significant weight gain was observed on day 28 at a dose of 2.5 mg/kg (p < 0.05). Ziprasidone did not affect food intake at any time point. A significant decrease in water intake was observed during the first week of treatment with 2.5 mg/kg ziprasidone (p < 0.05). Ziprasidone had no effect on intraperitoneal fat weight, uterine wet or dry weight, or plasma prolactin levels. All animals treated with ziprasidone exhibited a normal four-day estrous cycle. In rats, embryotoxicity (decreased fetal weight, delayed skeletal ossification) was observed after administration of ziprasidone at doses of 10 to 160 mg/kg/day during organogenesis or throughout gestation, but no teratogenicity was found. Doses of 40 and 160 mg/kg/day were associated with maternal toxicity. Ziprasidone has been tested in the Ames bacterial mutation assay, in vitro mammalian cell gene mutation mouse lymphoma assay, and in vivo mouse bone marrow chromosomal aberration assay. In the Ames assay, a reproducible mutagenic response was observed against a strain of Salmonella typhimurium without metabolic activation. The in vitro mammalian cell gene mutation assay yielded positive results.

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Interactions
In vivo studies showed that co-administration of ziprasidone with carbamazepine reduced its AUC by approximately 35%, and co-administration with ketoconazole increased its AUC by approximately 35-40%, but cimetidine or antacids had no effect on the pharmacokinetics of ziprasidone.
Pharmacokinetic/pharmacodynamic studies of ziprasidone with other QT-prolonging drugs have not been conducted. The possibility of additive effects of ziprasidone with other QT-prolonging drugs cannot be ruled out. Therefore, ziprasidone should not be used concomitantly with dofetilide, sotalol, quinidine, other Class Ia and III antiarrhythmic drugs, mesoliderazine, thioridazine, chlorpromazine, fluperidone, pimozide, sparfloxacin, gatifloxacin, moxifloxacin, halofantroline, mefloquine, pentamifil, arsenic trioxide, levomethadone acetate, dolasetron mesylate, probucol, or tacrolimus. Ziprasidone is contraindicated with drugs whose pharmacodynamic effect is QT prolongation, and which are listed as contraindicated in the full prescribing information or described as a boxed or bold warning.
Because ziprasidone has the potential to induce hypotension, it may enhance the effects of certain antihypertensive drugs. Ziprasidone may antagonize the effects of levodopa and dopamine agonists. For more complete (8 items) data on drug interactions of ziprasidone, please visit the HSDB record page.

[1]. 5-HT(1A) receptor activation contributes to ziprasidone-induced dopamine release in the rat prefrontal cortex. Biol Psychiatry. 2000;48(3):229-237.

[2]. Block of hERG channel by ziprasidone: biophysical properties and molecular determinants. Biochem Pharmacol. 2006 Jan 12;71(3):278-86.

[3]. The effect of ziprasidone on body weight and energy expenditure in female rats. Metabolism. 2012 Jun;61(6):787-93.

Therapeutic Uses
Antidote; Dopamine antagonist; Serotonin antagonist Ziprasidone is indicated for the treatment of schizophrenia. The efficacy of oral ziprasidone has been demonstrated in four short-term (4-week and 6-week) controlled trials in hospitalized adult patients with schizophrenia and in one maintenance therapy trial in hospitalized adult patients with stable schizophrenia. /US Product Label Includes/ Ziprasidone can be used as monotherapy for the acute phase of manic or mixed episodes associated with bipolar I disorder. Its efficacy has been demonstrated in two 3-week monotherapy studies in adult patients. /US Product Label Includes/ Ziprasidone can be used as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar I disorder. Its efficacy has been demonstrated in one maintenance therapy trial in adult patients. The efficacy of ziprasidone as monotherapy for maintenance treatment of bipolar I disorder has not been systematically evaluated in controlled clinical trials. /US Product Label Contains/

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Drug Warning
/Black Box Warning/ Warning: Increased Mortality in Patients with Alzheimer's Disease-Related Psychosis. Patients with Alzheimer's disease-related psychosis receiving antipsychotic medication have an increased risk of death. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that the risk of death in patients treated with medication was 1.6 to 1.7 times higher than in those treated with placebo. These trials primarily involved patients taking atypical antipsychotics. In a typical 10-week controlled trial, the mortality rate in patients treated with medication was approximately 4.5%, compared to approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular diseases (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). Observational studies have shown that, similar to atypical antipsychotics, treatment with conventional antipsychotics may increase mortality. The extent to which the increased mortality observed in observational studies is attributable to the antipsychotics themselves, rather than certain characteristics of the patients, is currently unclear. Ziprasidone is not approved for the treatment of patients with dementia-related psychosis. Contraindications include: a known history of QT interval prolongation (including congenital long QT syndrome), recent acute myocardial infarction, or decompensated heart failure. Concurrent use of other medications that prolong the QT interval. Known hypersensitivity to ziprasidone. Elderly patients with dementia-related psychosis treated with atypical antipsychotics appear to have a higher risk of death compared to those receiving placebo. An analysis of 17 placebo-controlled trials (mean duration 10 weeks) showed that the mortality rate in elderly patients treated with atypical antipsychotics (e.g., aripiprazole, olanzapine, quetiapine, risperidone) was approximately 1.6 to 1.7 times higher than in the placebo group. In typical 10-week controlled trials, the mortality rate was approximately 4.5% in the drug treatment group and approximately 2.6% in the placebo group. Although the causes of death varied, most deaths appeared to be related to cardiovascular disease (e.g., heart failure, sudden death) or infectious diseases (e.g., pneumonia). The manufacturer states that ziprasidone is not approved for the treatment of dementia-related psychosis.
QT interval prolongation can lead to ventricular arrhythmias (e.g., torsades de pointes) and/or sudden death. One study showed that oral ziprasidone prolongs the QT interval on an electrocardiogram by an average of 9-14 milliseconds, higher than patients taking risperidone, olanzapine, quetiapine, or haloperidol, but about 14 milliseconds less than patients taking thioridazine. …High-risk groups for torsades de pointes and/or sudden death include: patients with bradycardia, hypokalemia, or hypomagnesemia; patients taking other medications that prolong the QT interval; and patients with congenital QT interval prolongation. The manufacturer states that patients with congenital QT interval prolongation or a history of arrhythmias, as well as patients currently receiving other medications that prolong the QT interval, should avoid using ziprasidone.
For more complete data on drug warnings for ziprasidone (28 in total), please visit the HSDB record page.

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Pharmacodynamics
Ziprasidone is classified as a "second-generation" or "atypical" antipsychotic drug. It is a dopamine and 5-HT2A receptor antagonist with unique receptor binding properties. As mentioned earlier, ziprasidone has an extremely high 5-HT2A/D2 affinity ratio. In addition to the 5-HT2A receptor, it can bind to a variety of serotonin receptors and block monoamine transporters, thereby preventing the reuptake of 5-HT and NE. On the other hand, ziprasidone has lower affinity for muscarinic cholinergic M1 receptors, histamine H1 receptors, and α1-adrenergic receptors.

C21H21CLN4OS

412.94

412.11

C, 61.08; H, 5.13; Cl, 8.58; N, 13.57; O, 3.87; S, 7.76

146939-27-7

Ziprasidone-d8; 1126745-58-1; Ziprasidone hydrochloride monohydrate; 138982-67-9; Ziprasidone hydrochloride; 122883-93-6; Ziprasidone mesylate trihydrate; 199191-69-0; Ziprasidone mesylate; 185021-64-1

60854

White to off-white solid powder

1.4±0.1 g/cm3

554.8±50.0 °C at 760 mmHg

213-215°C

289.3±30.1 °C

0.0±1.5 mmHg at 25°C

1.681

4

1

5

4

28

573

0

ClC1C([H])=C2C(C([H])([H])C(N2[H])=O)=C([H])C=1C([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C2C3=C([H])C([H])=C([H])C([H])=C3SN=2)C([H])([H])C1([H])[H]

MVWVFYHBGMAFLY-UHFFFAOYSA-N

InChI=1S/C21H21ClN4OS/c22-17-13-18-15(12-20(27)23-18)11-14(17)5-6-25-7-9-26(10-8-25)21-16-3-1-2-4-19(16)28-24-21/h1-4,11,13H,5-10,12H2,(H,23,27)

5-[2-[4-(1,2-benzothiazol-3-yl)piperazin-1-yl]ethyl]-6-chloro-1,3-dihydroindol-2-one

CP 88059; CP88059; CP-88,059-01; CP88059 hydrochloride; CP-88059; CP-88,059; Ziprasidone HCl; Geodon; Zeldox; Zipwell

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)

DMSO: ~13.5 mg/mL (~32.7 mM)

Solubility in Formulation 1: ≥ 1.35 mg/mL (3.27 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 13.5 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 2: ≥ 1.35 mg/mL (3.27 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 13.5 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: ≥ 1.35 mg/mL (3.27 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 13.5 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.)