Benztropine has been shown to undergo metabolism mainly marked by N-oxidation, N-dealkylation and ring hydroxylation. The extensive metabolism of benztropine produces eight phase-I metabolites plus four glucuronide conjugates.
Following oral administration of benztropine (10 mg/kg, body weight), the phase I metabolites, benztropine N-oxide, N-desmethylbenztropine, tropine, 4'-hydroxybenz- tropine, N-desmethyl-4'-hydroxybenztropine, 4'-hydroxvbenztropine N-oxide and methoxy-4'-hydroxybenztropine, together with unmetabolized benztropine, were isolated and identified in rat urine and bile by GC-electron impact mass spectrometry (EI GC/MS), microcolumn LC-electrospray mass spectrometry (ES LC/MS) and HPLC followed by MS analysis. The mass spectra and chromatographic properties of isolated N-desmethylbenztropine, benztropine N-oxide and tropine were confirmed by comparison with authentic reference standards. Sufficient quantities of 4'-hydroxybenztropine and N-desmethyl-4'-hydroxybenztropine were isolated from the urine by tlc and examined by 1H-nmr, ES/MS and EI/MS. The structure of the methoxy-4'-hydroxybenztropine metabolite was determined by EI/MS. 4'-Hydroxybenztropine N-oxide was identified by reacting it with a reducing agent, titanous chloride, to form 4'-hydroxybenztropine, which was then confirmed by comparing its EI/MS and ES/MS behaviour with a previously isolated and 1H-nmr-authenticated sample. In addition, four intact glucuronide conjugates of benztropine were also characterized in bile and urine as phase II metabolites, including 4'-O-glucuronylbenzotropine, N-desmethyl-4'-O-glucuronylbenztropine, methoxy-4'-O-glucuronylbenztropine and 4'- O-glucuronylbenztropine N-oxide by hplc followed by ES/MS analysis. These results provide the first direct evidence of the presence of these metabolites of benztropine in rat.
Benztropine has not been reported to cause serum aminotransferase elevations, but it has not been evaluated for effects on serum enzyme levels in a prospective manner. Despite its use for more than 50 years, there have been no reports of benztropine liver injury in the literature and it must be a very rare cause of liver injury, if it occurs at all. Absense of liver injury is typical of anticholinergic agents and may relate to the low doses used (less than 10 mg daily).
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Drug Class: Antiparkinson Agents, Anticholinergic Agents
Other Drugs in the Subclass, Anticholinergic Agents: Biperiden, Trihexyphenidyl
参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今天，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今天2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007
M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015
Oral administration of 1.5 mg of benztropine is slowly absorbed in the gastrointestinal tract and it reaches a peak concentration of 2.5 ng/ml in about 7 hours. It has an approximate oral bioavailability of 29%.
Benztropine is expected to present a large volume of distribution between 12-30 L/kg.
来源:DrugBank
吸收、分配和排泄
清除
广泛的药效学或药代动力学研究尚未进行。
Extensive pharmacodynamic or pharmacokinetic studies have not been performed.
来源:DrugBank
文献信息
Methods and compositions for treating degenerative and ischemic disorders
申请人：The General Hospital Corporation
公开号：US10322122B2
公开（公告）日：2019-06-18
Model systems have shown that shifting a cell's reliance from oxidative phosphorylation (OXPHOS) to glycolysis can protect against cell death. Exploiting the therapeutic potential of this strategy, however, has been limited by the lack of clinically safe agents that remodel energy metabolism. The present invention identifies non-toxic small molecules (e.g., drug-like compounds) that are capable of modulating oxidative metabolism. One identified compound comprises meclizine. As described herein, meclizine, and its enantiomer S-meclizine, redirects OXPHOS to glycolysis. Such compounds could be protective or therapeutic in degenerative disorders such as diabetes, Huntington's, Parkinson's, and Alzheimer's disease and/or ischemic disorders including, but not limited to, stroke, heart attack, or reperfusion injuries.
4',4''-SUBSTITUTED 3ALPHA-(DIPHENYLMETHOXY)TROPANE ANALOGS FOR TREATMENT OF MENTAL DISORDERS
申请人：Phase 2 Discovery, Inc.
公开号：EP1624845A2
公开（公告）日：2006-02-15
SUBSTITUTED BENZTROPINE ANALOGS FOR TREATMENT OF DEMENTIA
申请人：P2D, Inc.
公开号：EP2925309A1
公开（公告）日：2015-10-07
METHODS AND COMPOSITIONS FOR TREATING DEGENERATIVE AND ISCHEMIC DISORDERS
申请人：The General Hospital Corporation
公开号：US20180071279A1
公开（公告）日：2018-03-15
Model systems have shown that shifting a cell's reliance from oxidative phosphorylation (OXPHOS) to glycolysis can protect against cell death. Exploiting the therapeutic potential of this strategy, however, has been limited by the lack of clinically safe agents that remodel energy metabolism. The present invention identifies non-toxic small molecules (e.g., drug-like compounds) that are capable of modulating oxidative metabolism. One identified compound comprises meclizine. As described herein, meclizine, and its enantiomer S-meclizine, redirects OXPHOS to glycolysis. Such compounds could be protective or therapeutic in degenerative disorders such as diabetes, Huntington's, Parkinson's, and Alzheimer's disease and/or ischemic disorders including, but not limited to, stroke, heart attack, or reperfusion injuries.
[EN] 4',4''-SUBSTITUTED 3 alpha -(DIPHENYLMETHOXY)TROPANE ANALOGS FOR TREATMENT OF MENTAL DISORDERS<br/>[FR] ANALOGUES DE 3 DOLLAR G(A)-(DIPHENYLMETHOXY)TROPANE SUBSTITUE EN 4',4'' POUR LE TRAITEMENT DE TROUBLES MENTAUX
申请人：PHASE 2 DISCOVERY INC
公开号：WO2004062610A2
公开（公告）日：2004-07-29
The present invention describes a method for the treatment of attention deficit hyperactivity disorder (ADHD), conduct disorder, alcohol addiction, tobacco addiction, nicotine addiction, parkinsonim including Parkinson's disease, female and male orgasmic disorders, female and male sexual arousal disorders, hypoactive sexual desire disorder, and disorders characterized by anxiety and/or depression. In this method, a therapeutically effective, nontoxid dose of a 4',4''-substituted 3α-(diphenylmethoxy)tropane analog or a pharmaceutically acceptable salt thereof is administered to the patient in need of such treatment.
