About 50% of the circulating species in plasma have been identified. The predominant species was asenapine N+-glucuronide; others included N-desmethylasenapine, N-desmethylasenapine N-carbamoyl glucuronide, and unchanged asenapine in smaller amounts. Asenapine activity is primarily due to the parent drug.
The metabolism and excretion of asenapine [(3aRS,12bRS)-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenzo[2,3:6,7]-oxepino [4,5-c]pyrrole (2Z)-2-butenedioate (1:1)] were studied after sublingual administration of (14)C-asenapine to healthy male volunteers. ... Metabolic profiles were determined in plasma, urine, and feces using high-performance liquid chromatography with radioactivity detection. Approximately 50% of drug-related material in human plasma was identified or quantified. The remaining circulating radioactivity corresponded to at least 15 very polar, minor peaks (mostly phase II products). Overall, >70% of circulating radioactivity was associated with conjugated metabolites. Major metabolic routes were direct glucuronidation and N-demethylation. The principal circulating metabolite was asenapine N(+)-glucuronide; other circulating metabolites were N-desmethylasenapine-N-carbamoyl-glucuronide, N-desmethylasenapine, and asenapine 11-O-sulfate. In addition to the parent compound, asenapine, the principal excretory metabolite was asenapine N(+)-glucuronide. Other excretory metabolites were N-desmethylasenapine-N-carbamoylglucuronide, 11-hydroxyasenapine followed by conjugation, 10,11-dihydroxy-N-desmethylasenapine, 10,11-dihydroxyasenapine followed by conjugation (several combinations of these routes were found) and N-formylasenapine in combination with several hydroxylations, and most probably asenapine N-oxide in combination with 10,11-hydroxylations followed by conjugations. In conclusion, asenapine was extensively and rapidly metabolized, resulting in several regio-isomeric hydroxylated and conjugated metabolites.
Liver test abnormalities occur in 1% to 2.5% of patients receiving asenapine, but similar rates are reported with placebo therapy (0.6% to 1.3%) and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There has been a single case report of cholestatic serum enzyme elevations arising 3 to 4 weeks after starting asenapine, resolving within a month of stopping. Thus, asenapine may be a rare cause of mild cholestatic liver injury.
◉ Summary of Use during Lactation:No information is available on the use of asenapine during breastfeeding. If asenapine is required by the mother, it is not a reason to discontinue breastfeeding. However, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants: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 asenapine was not reported.
◉ Effects on Lactation and Breastmilk:Galactorrhea has been reported with asenapine according to the manufacturer. Hyperprolactinemia appears to be the cause of the galactorrhea. The hyperprolactinemia is caused by the drug's dopamine-blocking action in the tuberoinfundibular pathway. The maternal 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 had primarily 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 asenapine was not reported.
来源:Drugs and Lactation Database (LactMed)
毒理性
相互作用
Potential pharmacologic interaction (possible disruption of body temperature regulation); use asenapine with caution in patients concurrently receiving drugs with anticholinergic activity.
可能的药物相互作用（可能干扰体温调节）；在接受具有抗胆碱活性的药物的患者中谨慎使用阿塞那平。
Potential pharmacologic interaction (possible disruption of body temperature regulation); use asenapine with caution in patients concurrently receiving drugs with anticholinergic activity.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
相互作用
Potential pharmacologic interaction (additive CNS and respiratory depressant effects). Use with caution with other drugs that can produce CNS depression. Avoid use of alcohol during asenapine therapy.
可能的药物相互作用（增加中枢神经系统和呼吸抑制的效果）。与其他可能引起中枢神经系统抑制的药物一起使用时应谨慎。在阿塞纳平治疗期间避免使用酒精。
Potential pharmacologic interaction (additive CNS and respiratory depressant effects). Use with caution with other drugs that can produce CNS depression. Avoid use of alcohol during asenapine therapy.
Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the corrected QT (QTc) interval, including class Ia antiarrhythmics (e.g., quinidine, procainamide), class III antiarrhythmics (e.g., amiodarone, sotalol), some antipsychotic agents (e.g., chlorpromazine, thioridazine, haloperidol, olanzapine, pimozide, paliperidone, quetiapine, ziprasidone), some antibiotics (e.g., gatifloxacin, moxifloxacin), and tetrabenazine.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
阿塞那平通过舌下给药，因为口服给药后观察到生物利用度较低（小于2%）和广泛的首过代谢。
Asenapine is administered sublingually because of the low bioavailability (less than 2%) and extensive first-pass metabolism observed following oral administration.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
药物舌下片在舌下、舌上和颊粘膜处迅速吸收，峰值血药浓度在0.5-1.5小时内出现。
Sublingual tablets of the drug are rapidly absorbed in the sublingual, supralingual, and buccal mucosa following sublingual administration, with peak plasma concentrations occurring within 0.5-1.5 hours.
The absolute bioavailability of sublingual asenapine (5 mg) is 35%. Steady-state plasma concentrations are reached within 3 days with twice-daily sublingual administration.
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
在服用单次5毫克阿塞纳平后，平均Cmax大约为4 ng/mL，在平均tmax为1小时时观察到。
Following a single 5-mg dose of asenapine, the mean Cmax was approximately 4 ng/mL and was observed at a mean tmax of 1 hour.
[EN] NOVEL PROCESS FOR THE PREPARATION OF ASENAPINE<br/>[FR] NOUVEAU PROCÉDÉ DE PRÉPARATION D'ASÉNAPINE
申请人：ALEMBIC PHARMACEUTICALS LTD
公开号：WO2013061247A1
公开（公告）日：2013-05-02
The present invention relates to a novel process for the preparation of trans-5-chloro-2- methyl-2,3,3a,12b- tetrahydro-1H-dibenz [2,3:6,7] oxepino[4,5-c] pyrrole (Asenapine) of formula (I). It also relates to novel intermediates i.e. 2-[(E)-2-(2-bromophenyl)ethenyl]-4-nitrophenyl acetate of formula (V), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenyl acetate of formula (VI), 2-[(3S,4S)-4-(2-bromophenyl)-1-methylpyrrolidin-3-yl]-4-nitrophenol of formula (VII), 5-nitro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (VIII) and 5-amino-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole of formula (IX) are useful for the preparation of Asenapine salts of formula (I).
PROCESS FOR THE PREPARATION OF ASENAPINE AND INTERMEDIATE PRODUCTS USED IN SAID PROCESS
申请人：Kemperman Gerardus Johannes
公开号：US20080009619A1
公开（公告）日：2008-01-10
The invention relates to a novel process for the preparation of asenapine, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, as well as to novel intermediate products for use in said process.
Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole
申请人：Kemperman Johannes Gerardus
公开号：US20060229352A1
公开（公告）日：2006-10-12
Disclosed are novel amino acid derivatives of formula (I) and (II)
processes for the preparation thereof, and their use in the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino-[4,5-c]pyrrole.
Monoamine neurotransmitters such as serotonin, dopamine, histamine, and noradrenaline have important and varied physiological functions and similar chemical structures. Representing important pharmaceutical drug targets, the corresponding G-protein-coupled receptors (termed aminergic GPCRs) belong to the class of cell membrane receptors and share many levels of similarity as well. Given their pharmacological
[EN] PROCESS FOR THE PREPARATION OF ASENAPINE AND INTERMEDIATE PRODUCTS USED IN SAID PROCESS<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ASÉNAPINE ET PRODUITS INTERMÉDIAIRES UTILISÉS DANS LEDIT PROCÉDÉ
申请人：ORGANON NV
公开号：WO2009087058A1
公开（公告）日：2009-07-16
The invention relates to a novel process for the preparation of asenapine, i.e. trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole, as well as to novel intermediate products for use in said process.
