He H, McKay G, Midha K K
College of Pharmacy and Nutrition University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Xenobiotica. 1995 Aug;25(8):857-72. doi: 10.3109/00498259509061899.
Following oral administration of benztropine (IO 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.
口服苯海索（10毫克/千克体重）后，通过气相色谱-电子轰击质谱（EI GC/MS）、微柱液相色谱-电喷雾质谱（ES LC/MS）和高效液相色谱-质谱分析，在大鼠尿液和胆汁中分离并鉴定出了I相代谢产物，包括苯海索N-氧化物、N-去甲基苯海索、托品、4'-羟基苯海索、N-去甲基-4'-羟基苯海索、4'-羟基苯海索N-氧化物和甲氧基-4'-羟基苯海索，以及未代谢的苯海索。通过与真实参考标准品比较，证实了分离出的N-去甲基苯海索、苯海索N-氧化物和托品的质谱和色谱特性。通过薄层层析从尿液中分离出足够量的4'-羟基苯海索和N-去甲基-4'-羟基苯海索，并通过1H-核磁共振、电喷雾质谱和电子轰击质谱进行检测。甲氧基-4'-羟基苯海索代谢产物的结构通过电子轰击质谱确定。4'-羟基苯海索N-氧化物通过与还原剂氯化亚钛反应生成4'-羟基苯海索进行鉴定，然后通过将其电子轰击质谱和电喷雾质谱行为与先前分离并经1H-核磁共振鉴定的样品进行比较来确认。此外，还通过高效液相色谱-电喷雾质谱分析在胆汁和尿液中鉴定出了四种苯海索的完整葡萄糖醛酸结合物作为II相代谢产物，包括4'-O-葡萄糖醛酸基苯海索、N-去甲基-4'-O-葡萄糖醛酸基苯海索、甲氧基-4'-O-葡萄糖醛酸基苯海索和4'-O-葡萄糖醛酸基苯海索N-氧化物。这些结果首次直接证明了大鼠体内存在这些苯海索代谢产物。
