Aripiprazole

Absorption

Tablet: Aripiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 3 hours to 5 hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be administered with or without food. Administration of a 15 mg ABILIFY tablet with a standard high-fat meal did not significantly affect the Cmax or AUC of aripiprazole or its active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole and 12 hours for dehydro-aripiprazole.
Oral Solution: Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher than that from the tablet formulation. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution-to-tablet ratios of geometric mean Cmax and AUC values were 122% and 114%, respectively. The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional between the doses of 5 mg to 30 mg.
Extended-release injectable suspension, bimonthly injection: Aripiprazole absorption into the systemic circulation is prolonged following gluteal intramuscular injection due to the low solubility of aripiprazole particles. The release profile of aripiprazole from ABILIFY ASIMTUFII results in sustained plasma concentrations over 2 months following gluteal injection(s). Following multiple doses, the median peak:trough ratio for aripiprazole following an ABILIFY ASIMTUFII dose is 1.3, resulting in a flat plasma concentration profile with Tmax ranging between 1 to 49 days following multiple gluteal administrations of 960 mg.

Description

Aripiprazole was launched for the treatment of psychoses including schizophrenia and offers a novel mechanism of action as a partial D₂ receptor agonist. Aripiprazole can be synthesized in three steps beginning by the condensation of 7-hydroxy-1,2,3,4- tetrahydroquinolin-2-one with 1 ,Cdibromobutane followed by reaction with 1-(2,3- dichlorophenyl)piperazine. Aripiprazole is a significant D₂ agonist/antagonist, 5-HT₂ antagonist and 5-HT_1α agonist combined with minimal affinity for a,-adrenergic, H₁ and M₁ receptors. It has a low D4:D2 selectivity ratio and a D2:5-HT₂ affinity ratio that exceeds 15; resulting in different pharmacological characteristics compared to other atypical antipsychotics agents such as clozapine. In animal models, aripiprazole inhibits apomorphine-induced stereotypy without causing catalepsy and ptosis. Moreover, in contrast to classical antipsychotics that produce disabling movement disorders, aripiprazole does not cause an upregulation of D2 receptors or an increase in immediate early gene expression of e.g. the c-fos mRNA in the striatum. In patients with acute relapse of schizophrenia, treatment with aripiprazole provided significant improvement in both positive and negative syndrome scale (PANSS) total score in both short- and longterm evaluations. These results were comparable to those observed with haloperidol or risperidone; however, the early response rate was greater with aripiprazole. Aripiprazole was well tolerated with mild to moderate adverse events such as nausea, dizziness, somnolence and weight gain. The rates of extrapyramidal symptoms were lower than with haloperidol, prolactin levels increase has been uncommon and no significant Q-Tc interval prolongation was observed compared with placebo. Finally, studies suggested a minimal impact of aripiprazole administration on total cholesterol levels and on fasting blood sugar in contrast to other antipsychotics. Aripiprazole has a bioavailability of 87%, a t_max of 3-5 h and a half-life time of 48-68 h. Aripiprazole has been found to have linear kinetics and is mainly metabolized via the cytochrome systems CYP2D6 and CYP3A4. It has little effect on the blood levels of other medications; interaction with both lithium and divalproex sodium found minimal impact. Aripiprazole has also been studied in other psychiatric disorders, including bipolar disorders and has shown great efficacy.

Chemical properties

Colourless Flake Crystalline Solid

Originator

Otsuka (Japan)

The Uses of Aripiprazole

A deuterated version of Aripiprazole, a selective dopamine D2-receptor antagonist with dopamine autoreceptor agonist activity. Please note that users have reported separation of this compound and aripiprazole under normal-phase and reverse-phase

The Uses of Aripiprazole

A selective dopamine D2-receptor antagonist with dopamine autoreceptor agonist activity. Antipsychotic.

The Uses of Aripiprazole

cerebral vasodilator, antimotion

The Uses of Aripiprazole

For the treatment of schizophrenia and related psychotic disorders.

What are the applications of Application

Aripiprazole is a selective dopamine D2-receptor antagonist showing autoreceptor agonist activity

Background

Aripiprazole is an atypical antipsychotic orally indicated for the treatment of schizophrenia, bipolar I, major depressive disorder, irritability associated with autism, and Tourette's. It is also indicated as an injection for agitation associated with schizophrenia or bipolar mania. Aripiprazole exerts its effects through agonism of dopaminergic and 5-HT1A receptors and antagonism of alpha-adrenergic and 5-HT2A receptors. Aripiprazole was given FDA approval on November 15, 2002.

Indications

Aripiprazole is indicated for the treatment of acute manic and mixed episodes associated with bipolar I disorder, irritability associated with autism spectrum disorder, schizophrenia, and Tourette's disorder. It is also used as an adjunctive treatment of major depressive disorder.[L45859 An injectable formulation of aripiprazole is indicated for agitation associated with schizophrenia or bipolar mania. Finally, an extended-release, bimonthly injection formulation of aripiprazole is indicated for the treatment of adult schizophrenia and maintenance therapy for adult bipolar I disorder.

Definition

ChEBI: Aripiprazole is an N-arylpiperazine that is piperazine substituted by a 4-[(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)oxy]butyl group at position 1 and by a 2,3-dichlorophenyl group at position 4. It is an antipsychotic drug used for the treatment of Schizophrenia, and other mood disorders. It has a role as a H1-receptor antagonist, a serotonergic agonist, a second generation antipsychotic and a drug metabolite. It is a quinolone, a N-arylpiperazine, a N-alkylpiperazine, a dichlorobenzene, an aromatic ether and a delta-lactam.

Manufacturing Process

To a solution of 4.06 g of K2CO3 with 400 ml of water was added 40 g of 7- hydroxy-3,4-dihydrocarbostyril [1] and 158 g of 1,4-dibrombutane. The mixture was refluxed for 3 hours. Then it was extracted with dichloremethane, dried with anhydrous MgSO4, the solvent was removed by evaporation. The residue was purified by means of silica gel chromatography (eluent: dichloromethane) and recrystallized from n-hexane-ethanol to yield 50 g of 7- (4-bromobutoxy)-3,4-dihydrocarbostyril, mp 110.5°-110.0°C.
47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of NaJ in 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine (it was prepareted from 2,3-chloroaniline and di(2-bromoethyl)amine [1]) and 33 ml of triethylamine. The mixture was refluxed for 3 hours. After removing of the solvent, the residue was dissolved in chloroform, washed with water and dried with anhydrous MgSO4. The solvent was removed by evaporation, and residue was recrystallized from ethanol twice to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]- butoxy}-3,4-dihydrocarbostyril. Melting point: 139.0°-139.5°C.

brand name

Abilify (Otsuka).

Therapeutic Function

Antipsychotic

General Description

Aripiprazole (Abilify). The newest, longactingaripiprazole (an arylpiperazine quinolinone derivative),appears to be partial agonist of D₂ receptors (i.e., itstimulates certain D2 receptors while blocking others dependingon their locations in the brain and the concentrationof drug). Bioavailability of aripiprazole is around 87%, with peak plasma concentration attained at 3 to 5 hours afterdosing. It is metabolized by dehydrogenation, oxidative hydroxylation, and N-dealkylation, largelymediated by hepatic CYPs 3A4 and 2D6.
The diphenylbutylpiperidine class can be considered amodification of the fluorobutyrophenone class. Because oftheir high lipophilicity, the compounds are inherently longacting. Pimozide has been approved for antipsychotic use,and penfluridol has undergone clinical trials in the UnitedStates. Overall, side effects for the two compounds resemblethose produced by the fluorobutyrophenones.

General Description

Aripiprazole, (7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolone,is an atypical antipsychotic that is available in tablets(Abilify), orally disintegrating tablets (Abilify Discmelt), anda 1-mg/mL oral solution. Unlike the other atypical antipsychotics,aripiprazole exhibits partial agonist activity at D₂, D₃,D₄, and 5-HT_1A receptors, and antagonist action at 5-HT_2A receptors.Although aripiprazole exhibits a low incidence ofEPS, the compound occupies about 95% of striatal D₂ receptorsat therapeutic doses. Additionally, aripiprazole does nothave a fast rate of dissociation from D₂ receptors. Althoughthe mechanism of action of this compound remains to be elucidated,the atypical profile for aripiprazole may be related toits action at other monoamine receptors.The compoundis well absorbed with peak plasma levels occurring 3 to 5hours after oral administration. Food does not affect absorptionof aripiprazole. Aripiprazole is extensively metabolizedin the liver by the action of CYP2D6 and CYP3A4. The primarymetabolite in humans is dehydroaripiprazole. This metabolite represents about 40% of aripiprazoleat steady state.In the presence of CYP3A4 and CYP2D6 inhibitorsor inducers, dosage adjustments of aripiprazole maybe required. The mean elimination half-lives in extensive andpoor metabolizers are 75 hours and 146 hours, respectively.The major adverse effects of aripiprazole are headache, anxiety,and insomnia.Similar to other atypical antipsychotics,aripiprazole shows an increased risk in mortality in elderlypatients with dementia-related psychosis.Aripiprazoledemonstrates a different pharmacological profile from allother atypical antipsychotics.

Hazard

A poison.

Mechanism of action

Aripiprazole is a partial agonist at D2 and 5HT-1a receptors and an antagonist at 5HT-2a receptors. It has a high affinity for D2, D3, 5HT-1a and 5HT2a receptors, and a moderate affinity for D4, 5HT-2c, 5-HT7, alpha-1 adrenergic and H1 receptors. At the recommended dose, aripiprazole has no affinity for muscarinic receptors. It stabilises dopamine and serotonin in the nucleus ambiguus, ventral tegmental area and frontal cortex, thereby controlling positive, negative and cognitive symptoms of schizophrenia. Aripiprazole is functionally selective in intracellular signalling pathways; it requires more than 90% occupancy of D2 receptors to be clinically active and therefore does not produce excessive extrapyramidal symptoms. Aripiprazole selectively modulates the mesolimbic dopaminergic pathway.

Biochem/physiol Actions

Aripiprazole is a second generation atypical antipsychotic and anti-depressant with partial agonist activity at dopamine D2 and serotonin 5-HT1A receptors and antagonist activity at serotonin 5-HT2A receptors. Ki values are 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively, for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors. Aripiprazole is used in the treatment of schizophrenia.

Pharmacokinetics

Aripiprazole exhibits high affinity for dopamine D2 and D3, serotonin 5-HT1a and 5-HT2a receptors (Ki values of 0.34 nM, 0.8 nM, 1.7 nM, and 3.4 nM, respectively), moderate affinity for dopamine D4, serotonin 5-HT2c and 5-HT7, alpha1-adrenergic and histamine H1 receptors (Ki values of 44 nM, 15 nM, 39 nM, 57 nM, and 61 nM, respectively), and moderate affinity for the serotonin reuptake site (Ki=98 nM). Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors (IC50>1000 nM).

Clinical Use

Atypical antipsychotic:
Treatment of schizophrenia
Depression in bipolar disorder

Safety Profile

A poison by intravenous route.When heated to decomposition it emits toxic vapors ofNOx and Cl^-.

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone.
Antihypertensives: may enhance antihypertensive effect.
Alcohol and other CNS drugs: increased sedation and other related side effects.
Anti-arrhythmics: increased risk of ventricular arrhythmias with anti-arrhythmics that prolong the QT interval.
Antibacterials: concentration possibly reduced by rifabutin and rifampicin - increase dose of aripiprazole.
Antidepressants: fluoxetine and paroxetine possibly inhibit metabolism - reduce dose of aripiprazole; concentration possibly reduced by St John’s wort - increase aripiprazole dose; increased concentration of tricyclics.
Antiepileptics: antagonises anticonvulsant effect; concentration reduced by carbamazepine and possibly reduced by fosphenytoin, phenytoin, phenobarbital and primidone - increase dose of aripiprazole.
Antifungals: metabolism inhibited by ketoconazole and possibly by itraconazole - reduce dose of aripiprazole.
Antimalarials: avoid with artemether/lumefantrine.
Antipsychotics: possible increased risk of ventricular arrhythmias with risperidone.
Antivirals: metabolism possibly inhibited by atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, ritonavir, saquinavir and tipranavir - reduce dose of aripiprazole; concentration possibly reduced by efavirenz and nevirapine - increase dose of aripiprazole.
Anxiolytics and hypnotics: increased sedative effects.
Atomoxetine: increased risk of ventricular arrhythmias.
Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide.

Side Effects

Common side effects of Aripiprazole in children and adults include: uncontrollable twitching or jerky movements, feeling anxious or restless, feeling sick, upset or pain in the stomach, constipation (difficulty in having a bowel movement), dizziness, drowsiness, and blurred vision. Side effects that are more likely to occur in young people 13 years of age and older than in adults include: extreme tiredness and drowsiness, dry mouth, muscle twitching, dizziness, appetite increase and weight gain, restlessness, abdominal (belly) pain, and fast heartbeat. Rare adverse reactions may include neuroleptic malignant syndrome, abnormal liver function and jaundice, seizures and granulocytopenia.

Metabolism

Aripiprazole is metabolized primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug moiety in systemic circulation. At steady-state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.

Metabolism

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the main active moiety in systemic circulation. At steady state, dehydroaripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
Following a single oral dose of [14C]-aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.

storage

Store at -20°C

References

1) Green et al. (2004), Focus on aripiprazole; Curr. Med. Res. Opin., 20 207 2) Kikuchi et al. (1995), 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy)-3,4-dihydro-2(1H)-quinolinone (OPC-14597), a new putative antipsychotic drug with both presynaptic dopamine autoreceptor agonistic activity and postsynaptic D2 receptor antagonistic activity; J. Pharmacol. Exp. Ther., 274 329 3) Madhusoodanan et al. (2008), Management of psychosis in patients with Alzheimer’s disease: focus on aripiprazole; Clin. Interv. Aging, 3 491 4) Feltenstein et al. (2007), Aripiprazole blocks reinstatement of cocaine seeking in an animal model of relapse; Biol. Psychiatry, 61 582