非典型抗精神病新药阿立哌唑的合成

目的：研究非典型抗精神病药阿立哌唑的合成路线及工艺。方法：通过优化反应溶剂、反应温度、反应时间及加料方式，以1-(2，3-二氯苯基)哌嗪盐酸盐为起始原料，经N-溴丁基化和O-烃基化合成了阿立哌唑。结果：合成了目标化合物，总收率85％，其化学结构经元素分析、红外光谱、核磁共振氢谱及质谱确证。结论：该方法适合工业化生产。     

阿立哌唑的合成工艺

目的　考察阿立哌唑的合成路线。方法　以7-羟基- 3,4 -二氢- 2 (1H) -喹喏酮为原料,经O -溴丁基化和缩合反应合成阿立哌唑。结果　阿立哌唑总收率为81%,经元素分析、红外光谱确证化学结构正确。结论　该合成路线适于工业化生产。     

阿立哌唑的合成

7-羟基-3,4-二氢-2（1H）-喹诺酮和4-溴-1-丁醇经醚化制得7-（4-羟基丁氧基）-3,4-二氢-2（1H）-喹诺酮，再经磺酰化、1-（2，3-二氯苯基）哌嗪取代制得抗精神病药阿立哌唑，总收率77．5％。     

阿立哌唑治疗精神分裂症的临床评价

目的：评价国产阿立哌唑对精神分裂症的疗效与安全性。方法：80例精神分裂症患者随机分为2组：阿立哌唑组40例，给予阿立哌唑10～20mg·d~(-1)，po，qd；氯氮平组40例，给予氯氮平300～500mg·d~(-1)，po，Bid。采用阳性症状与阴性症状量表(PANSS)评价临床疗效、不良反应症状量表(TESS)评价不良反应，观察8周。结果：阿立哌唑治疗后PANSS总分减分率为50．4％，有效率为87．5％；氯氮平PANSS总分减分率为49．4％，有效率为85．0％。两组总体疗效相当(P＞0．05)。阿立哌唑对阴性症状起效较早。阿立哌唑组常见不良反应有锥体外系反应(EPS)(17．5％)、头痛(12．5％)、恶心呕吐(10％)，但与氯氮平组比较差异无显著性(P＞0．05)，且程度较轻，无血象及糖代谢异常；与氯氮平组较多的过度镇静(37．5％)、流延(45％)、便秘(25％)、体重增加(25％)比较差异有显著性(P＜0．05或P＜0．01)。结论：阿立哌唑是一种治疗精神分裂症安全有效的药物。     

阿立哌唑与利培酮治疗精神分裂症的临床疗效及对血清催乳素的影响

目的：比较阿立哌唑与利培酮治疗精神分裂症的临床疗效及对血清催乳素的影响。方法：2005年5月至2006年5月在我院治疗的80例精神分裂症患者，随机分为两组：阿立哌唑组（40例）和利培酮组（40例），阿立哌唑组给予阿立哌唑初始剂量10mg／d，2周末增至20～30mg／d，利培酮组给予利培酮初始剂量1mg,／d，2周末增至4—6mg／d。总疗程为8周。采用阳性和阴性症状量表（PANSS）、副反应量表（TESS）评定临床疗效及不良反应；采用化学发光法测定血清催乳素（PRL）水平。结果：经8周治疗，阿立哌唑组显效率72．5％；利培酮组显效率77、5％，两者差异无显著性（P〉0．05）。阿立哌唑组主要不良反应为：嗜睡，头痛，胃肠道反应，也可产生静坐不能，但未发现泌乳或闭经现象；利培酮组主要不良反应为：急性肌张力障碍、震颤、静坐不能、泌乳或闭经、体重增加等。利培酮组治疗8周后，血清PRL水平较治疗前明显升高，差异非常显著（P〈0．01），其中男性PRL升高3．5倍，女性PRL升高8倍；而阿立哌唑组血清PRL水平无变化。结论：阿立哌唑是一种较为安全、有效的抗精神病药物。     

阿立哌唑与利培酮治疗精神分裂症的临床对照研究

目的：比较阿立哌唑（奥哌）与利培酮治疗精神分裂症的疗效和副作用。方法：将83例符合CCMD-3-R诊断标准的精神分裂症及精神分裂症样精神病病人随机分为两组，分别给予阿立哌唑及利培酮治疗8周，采用阳性症状和阴性症状量表（PANSS）评价临床疗效，副反应量表（TESS）评价副反应。结果：治疗后两组PANSS总分及备因子分减分率无明显差异（P〉0.05）。阿立哌唑组有效率为95．23％，利培酮组有效率为95．12％。阿立哌唑与利培酮对精神分裂症均有较好的疗效，对精神分裂症阳性和阴性症状均有良好效果，阿立哌唑的副作用较小。结论：两种药物治疗精神分裂症的疗效相当，阿立哌唑无明显体重增加、闭经和溢乳副作用，较利培酮具有优势，但胃肠道反应较多。     

抗精神病药阿立哌唑的合成工艺改进

目的改进抗精神病药阿立哌唑的合成工艺。方法以间氨基苯甲醚为原料,经酰胺化、傅-克烃化、醚化、N-烷基化四步反应合成阿立哌唑。结果通过优化条件合成了阿立哌唑,总收率40%,目标化合物的结构经元素分析、质谱、氢谱、红外光谱确证。结论改进后的工艺操作简便,易于控制,且节省了反应时间,降低了生产成本,更有利于工业化生产。     

阿立哌唑与利培酮治疗精神分裂症疗效对比

目的：观察阿立哌唑治疗精神分裂症的疗效及不良反应。方法：60例精神分裂症患者,随机分为两组,分别给予阿立哌唑与利培酮治疗,疗程6周。采用阳性与阴性症状量表（PANSS）、副反应量表（TESS）评定疗效及不良反应。结果：阿立哌唑组显效率为70％,利培酮组显效率为73,3％。利培酮组锥体外系反应稍高于阿立哌唑组。结论：阿立哌唑疗效与利培酮相似,锥体外系反应比利培酮少,是一利有效、安全的抗精神病药物。     

阿立哌唑治疗精神分裂症的临床疗效及不良反应观察

目的：探讨国产阿立哌唑片治疗精神分裂症的疗效和安全性。方法：阿立哌唑治疗精神分裂症患者30例．完成6周的疗程，以阳性和阴性症状量表（PANSS）和副反应量表（TESS）评定疗效和不良反应。结果：治疗第1，2，3，4，6周末PANSS总分较治疗前显著下降（P〈0．05），有效率为87．0％。不良反应多为轻度。结论：国产阿立哌唑片是治疗精神分裂症的安全有效的药物。     

抗精神病药阿立哌唑的药理、毒理和临床评价

阿立哌唑(aripiprazole，商品名Abilify)的化学名为7-[4-[4-(2，3-二氯苯基)-1-哌嗪基]丁氧基]-3，4-二氢喹诺酮，是口服给药的精神病治疗药物，与适量乳糖、玉米淀粉、微晶纤维素、羟丙基纤维素、硬脂酸镁等药用辅料处方制成片剂后使用，每片含阿立哌唑5mg、10mg、15mg、20mg或30mg。     

阿立哌唑的制备工艺研究

目的:优化阿立哌唑的制备工艺。方法:以7-羟基-3,4-二氢-2-(1H)-喹啉酮为起始原料,经与1,4-二溴丁烷醚化后,再与1-(2,3-二氯苯基)哌嗪缩合,制得阿立哌唑。结果:醚化时用丙酮替代DMF作溶剂,反应副产物减少;由中间体Ⅲ制备终产物Ⅰ原工艺采用萃取法纯化,溶剂消耗多,成本高,本文中改由直接大量多次水洗产品,操作简便,产物纯度符合要求,总收率达到71.3%。结论:优化后的制备工艺稳定可行,适合工业化生产要求。     

阿立哌唑的血药浓度与其治疗精神分裂症疗效的相关性分析

目的：探讨阿立哌唑在中国精神分裂症病人体内的血药浓度与临床疗效的关系。方法：采用高效液相色谱-质谱联用(HPLC-MS)的方法测定30例精神分裂症病人体内阿立哌唑的血浆药物浓度,疗效评定采用阳性与阴性症状量表(PANSS)评分,用SPSS 11．0统计软件包对血药浓度与疗效评分进行统计分析。结果：治疗wk1,2,3,4末的阿立哌唑血药峰浓度与wk 1,2,3,4末的PANSS减分率无相关性,而wk 3,4末的平均稳态谷浓度与wk 4末的PANSS减分率呈正相关(r＞0．500,P＜0．05)。同时,将稳态血药谷浓度分为小于350．0μg·L~(-1)组和大于350．0μg·L~(-1)组病人的疗效进行比较,结果前者的PANSS减分率明显低于后者,两者的差异有统计学意义(P＜0．05)。结论：根据本实验研究结果,初步得出阿立哌唑的临床疗效与其稳态谷浓度高低有关,其稳态谷浓度在350．0μg·L~(-1)以上时,疗效较好。     

Aripiprazole: a review of its use in schizophrenia and schizoaffective disorder

Aripiprazole, a quinolinone derivative, is an atypical antipsychotic drug indicated for the treatment of adult patients with schizophrenia. Aripiprazole 10 or 15 mg once daily is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. Although aripiprazole has only been directly compared with haloperidol and olanzapine in treatment-responsive patients to date, current data generally indicate that aripiprazole has a beneficial profile in terms of a low potential for bodyweight gain. Dosage titration is not necessary and the drug is effective in the first few weeks of treatment. Head-to-head comparative trials with atypical antipsychotic agents are required, as are long-term (> or =1 year) studies, to fully define the position of aripiprazole in relation to other antipsychotic drugs. Aripiprazole is a valuable new therapeutic option in the management of patients with schizophrenia. PHARMACOLOGICAL PROPERTIES: Aripiprazole is a quinolinone derivative with a high affinity for dopamine D2 and D3 receptors, and serotonin 5-HT1A, 5-HT2A and 5-HT2B receptors. The mechanism of action of aripiprazole is not yet known, but evidence suggests that its efficacy in the treatment of the positive and negative symptoms of schizophrenia and its lower propensity for extrapyramidal symptoms (EPS) may be attributable to aripiprazole's partial agonist activity at dopamine D2 receptors. At serotonin 5-HT1A receptors, in vitro studies have shown that aripiprazole acts as a partial agonist whereas at serotonin 5-HT2A receptors aripiprazole is an antagonist. The main active metabolite, dehydro-aripiprazole, has affinity for dopamine D2 receptors and thus has some pharmacological activity similar to that of the parent compound. Aripiprazole is rapidly absorbed after oral administration. The mean time to peak plasma concentration is 3 hours following multiple-dose administration of aripiprazole 10 or 15 mg and the absolute oral bioavailability of the drug is 87%. Steady-state plasma drug concentrations are achieved by 14 days; however, the drug appears to accumulate over this period, since mean peak plasma concentration and mean area under the plasma concentration-time curve values of aripiprazole 10 or 15 mg/day are 4-fold greater on day 14 than on day 1. This accumulation may be expected, since the mean elimination half-life of a single dose of aripiprazole is about 75 hours. Aripiprazole has extensive extravascular distribution and more than 99% of aripiprazole and dehydro-aripiprazole (the main active metabolite of aripiprazole) is bound to plasma protein. Elimination of the drug is primarily hepatic; the cytochrome P450 (CYP) 3A4 and CYP2D6 enzyme systems transform aripiprazole to dehydro-aripiprazole, with the latter enzyme system subject to genetic polymorphism. Thus, dosage adjustment of aripiprazole is necessary when it is coadministered with CYP3A4 and CYP2D6 inhibitors (since aripiprazole concentration is increased) and with inducers of CYP3A4 (since aripiprazole concentration is decreased). THERAPEUTIC EFFICACY: The efficacy of aripiprazole has been demonstrated in patients with schizophrenia or schizoaffective disorder. In general, significant reductions from baseline in mean Positive and Negative Syndrome Scale total, positive and negative symptom scores, and Clinical Global Impression Severity of Illness scores were observed in patients with acute relapse of chronic schizophrenia or schizoaffective disorder receiving recommended (10 or 15 mg/day) or higher-than-recommended (20 or 30 mg/day) dosages of aripiprazole versus those receiving placebo in three well controlled, short-term trials. No additional therapeutic benefit was observed at the higher-than-recommended dosages. The drug is effective as early as the first or second week of treatment. The efficacy of aripiprazole was maintained for up to 52 weeks. The drug was significantly more effective than placebo in preventing relapse in patients with stable chronic schizophrenia in a 26-week, randomised trial. In a 52-week trial in patients with acute relapse of schizophrenia, the percentage of responders maintaining a response at study end was 77% of aripiprazole versus 73% of haloperidol recipients. Aripiprazole may improve cognitive function. In a nonblind, 26-week trial, patients with chronic schizophrenia receiving aripiprazole 30 mg/day experienced similar (general cognitive function) or better (verbal learning) changes from baseline in the neurocognitive parameters evaluated compared with recipients of olanzapine 10-15 mg/day. TOLERABILITY: Aripiprazole 10-30 mg/day was generally well tolerated. The tolerability profile of aripiprazole was broadly similar to that observed with placebo in a meta-analysis of short-term trials in patients with acute relapse of schizophrenia or schizoaffective disorder and in a 26-week trial in patients with chronic stable schizophrenia. The most frequent treatment-emergent adverse events included insomnia and anxiety, and additionally, headache and agitation (in short-term trials) or akathisia and psychosis (in a 52-week trial). In general, the drug was associated with a placebo-level incidence of EPS and EPS-related adverse events. Significantly fewer aripiprazole recipients experienced EPS-related adverse events than haloperidol recipients in a 52-week trial. Changes in severity of EPS were minimal and usually no different from those observed with placebo. Moreover, there was less severe EPS in the aripiprazole group than the haloperidol group in a long-term trial. Treatment-emergent tardive dyskinesia was reported in only 0.2% of patients receiving aripiprazole (short-term trials), an incidence similar to that seen in placebo recipients (0.2%). Aripiprazole has a low propensity to cause clinically significant bodyweight gain, hyperprolactinaemia or corrected QT interval prolongation in patients with schizophrenia or schizoaffective disorder. In addition, there were no clinically relevant differences in mean changes from baseline in measures of diabetes and dyslipidaemia between the aripiprazole or placebo groups in a 26-week, placebo-controlled trial.     

Effect of combination of aripiprazole with carbamazepine and fluvoxamine on liver functions in experimental animals

Objectives:

Aripiprazole, a new atypical antipsychotic drug extensively metabolized by enzyme CYP3A4, is found to produce asymptomatic elevation of serum transaminase levels on long-term treatment. The present study aims to evaluate the hepatotoxic effect of aripiprazole when coprescribed with carbamazepine and fluvoxamine.

Materials and Methods:

The rats were subjected to chronic treatment with two different doses, therapeutic dose (TD) and maximum therapeutic dose (MTD), of aripiprazole in combination with carbamazepine and fluvoxamine. The changes in hepatic function was assessed by various biochemical liver enzyme markers like serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase (ALP), total bilirubin, histological studies, and physical parameters (liver weight, liver volume, and body weight).

Results:

The combination of aripiprazole with fluvoxamine at both TD and MTD showed the hepatic damage and significant elevation in serum transaminase level which is supported by histological reports. The coadministration of aripiprazole with carbamazepine leads to significant decrease in blood concentration of aripiprazole possibly due to induction of enzyme CYP3A4 resulting in loss or reduction of clinical efficacy.

Conclusions:

There would be an accumulation of aripiprazole when coadministered with fluvoxamine, a known inhibitor of CYP3A4, leading to hepatic damage and reduction in aripiprazole when administered along with carbamazepine. Therefore, aripiprazole with fluvoxamine and carbamazepine should be coprescribed with caution. The patients should be monitored for signs of adverse effects like hepatic damage or decreased efficacy of these drugs.KEY WORDS: Aripiprazole, antipsychotic drug, carbamazepine, drug-drug interaction, fluvoxamine, hepatotoxicity     

Influence of CYP2D6, CYP3A4, CYP3A5 and ABCB1 Polymorphisms on Pharmacokinetics and Safety of Aripiprazole in Healthy Volunteers

The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P‐glycoprotein (P‐gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro‐aripiprazole, in 148 healthy volunteers from six bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC‐MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined. As the number of active CYP2D6 alleles decreased, AUC_0?t, C_max and t_1/2 of aripiprazole were higher and clearance of aripiprazole, AUC_0?t of dehydro‐aripiprazole and ratio dehydro‐aripiprazole/aripiprazole were lower. AUC_0?t of aripiprazole of poor metabolizer (PM) subjects was increased by 50% compared to extensive metabolizers (EM), and AUC_0?t of dehydro‐aripiprazole was decreased by 33%. ABCB1 1236TT subjects had a lower clearance of aripiprazole (p = 0.023) and AUC_0?t (p = 0.039) and C_max of dehydro‐aripiprazole (p = 0.036) compared to C/C. CYP3A5*3/*3 subjects had a 10% lower ratio dehydro‐aripiprazole/aripiprazole than *1/*3 (p = 0.019). Adverse drug reactions (ADRs) had a directly proportional relationship with AUC_0?t of aripiprazole (p = 0.001), especially nausea/vomiting, which were more common in women (p = 0.005). Women and CYP3A5*1/*1 subjects showed more often dizziness (p = 0.034; p = 0.009). Pharmacokinetics of aripiprazole is affected by CYP2D6 phenotype but also by sex and C1236T (ABCB1 gene), while dehydro‐aripiprazole pharmacokinetics is affected by CYP2D6 and C1236T. The ratio dehydro‐aripiprazole/aripiprazole was influenced by CYP2D6 phenotype and CYP3A5*3. Concentrations of aripiprazole, sex, CYP3A5*3 and CYP2D6 were involved in the development of ADRs.     

Population pharmacokinetic modelling of aripiprazole and its active metabolite,dehydroaripiprazole, in psychiatric patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers.
• The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole.

WHAT THIS STUDY ADDS

• The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach.
• The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM.

AIMS

The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK).

METHODS

A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10–30 mg day¹).

RESULTS

A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h¹. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20–0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype.

CONCLUSIONS

This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated.     

Pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole in psychiatric patients

Aripiprazole is a new atypical antipsychotic drug with a partial agonist activity at dopamine 2 and serotonin 1A receptors. The metabolism of aripiprazole involves both cytochrome P450 2D6 (CYP2D6) and CYP3A4. This study investigated the pharmacokinetic variability of aripiprazole and the active metabolite dehydroaripiprazole on the basis of 155 drug monitoring samples from psychiatric patients treated with therapeutic doses of aripiprazole (10-30 mg/day). Serum concentrations of drug and metabolite were determined by liquid chromatographic and tandem mass spectrometric detection. Pharmacokinetic variability was expressed as the range in concentration/dose (C/D) ratios, and the effect of sex and occasionally coprescribed CYP2D6 or CYP3A4 inhibitors/inducers was studied. In addition, the dose-concentration relationship and combined interquartile range of concentrations obtained at low dose (10-15 mg/day) and high dose (20-30 mg/day) were described. Individual C/D ratios ranged 37-fold for aripiprazole, 78-fold for dehydroaripiprazole, and 27-fold for the active sum of aripiprazole + dehydroaripiprazole. Median C/D ratios in male and female patients differed by less than 15%, and none of the differences were significant (P > 0.14). Cases of concurrent CYP3A4 inducers/inhibitors were not found, but three patients were coprescribed the potent CYP2D6 inhibitors paroxetine or fluoxetine. No consistent difference in C/D ratio was observed in these three patients compared with the rest of the patients. There was a proportional dose-concentration relationship in the population, and the combined interquartile ranges were 230 to 960 nmol/L for aripiprazole and 330 to 1210 nmol/L for aripiprazole + dehydroaripiprazole. In conclusion, pharmacokinetic variability of aripiprazole is extensive in psychiatric patients but apparently not dependent on dose or sex. The variability of the pharmacologic active sum of aripiprazole + dehydroaripiprazole is 25% to 30% less than aripiprazole, suggesting that variability of aripiprazole is partly determined by metabolism to dehydroaripiprazole.     

阿立哌唑治疗酒精所致精神障碍

目的:探讨阿立哌唑对酒精所致精神障碍的临床疗效与安全性.方法:将62例患者随机分成两组,分别以阿立哌唑和奋乃静治疗,疗程4周.用阳性与阴性症状量表(PANSS),不良反应量表(TESS)评定疗效和不良反应.结果:阿立哌唑组有效率87.1%,奋乃静组67.7%,两组比较差异有显著性.结论:阿立哌唑对酒精所致精神障碍的疗效优于奋乃静,且不良反应少.     

Pharmacokinetics and tolerability of intramuscular, oral and intravenous aripiprazole in healthy subjects and in patients with schizophrenia

BACKGROUND AND OBJECTIVE: Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. SUBJECTS AND METHODS: Study 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the bioavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). MAIN OUTCOME MEASURES: The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. RESULTS: In study 1, the geometric mean values for the absolute bioavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the C(max) values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. CONCLUSION: More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.