新型抗心律失常药物α,α-二甲基-4-(α,α,β,β-四氟苯乙基)-苄胺（MK-251）在不同物种中的代谢产物的质谱鉴定

Mass spectral identification of the metabolites of alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)-benzylamine (MK-251), a novel antiarrhythmic agent, in various species.

作者信息

Zacchei A G, Rhodes R E, Christy M E

出版信息

Biomed Mass Spectrom. 1976 Dec;3(6):286-94. doi: 10.1002/bms.1200030607.

DOI:10.1002/bms.1200030607

Abstract

The identification of a number of metabolites of the novel antiarrhythmic agent, alpha,alpha-dimethyl-4-(alpha,alpha,beta,beta-tetrafluorophenethyl)benzylamine (MK-251), is presented. The compound is extensively metabolized by dog, monkey, baboon and man. Similar metabolic profiles were obtained for all species. Isolation and purification were accomplished by solvent extraction and chromatographic (column, gas and thin-layer) procedures. Gas chromatography, derivatization, infrared, nuclear magnetic resonance and particularly combined gas chromatography low and high resolution mass spectrometry techniques were employed to characterize the metabolites. The major urinary and plasma metabolites were identified as 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol and its glucuronide conjugate. Other metabolites characterized were: the N-glucuronide of MK-251; 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propene; 2-nitro-2-[4-)alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]propane; alpha,alpha-dimethyl-4(alpha,alpha,beta,beta-tetrafluorophenethyl)benzyl methyl ether; and 4-(alpha,alpha,beta,beta-tetrafluorophenethyl)acetophenone. The 0-methyl ether metabolite represents the first instance of in vivo alkylation of a tertiary alcohol. Tentative identification was made for the N-hydroxy analog of MK-251 and for the glycol analog of 2-[4-(alpha,alpha,beta,beta-tetrafluorophenethyl)phenyl]-2-propanol. The observed pharmacological response appears to result mainly from MK-251 and not from the four metabolites.

摘要

本文介绍了新型抗心律失常药物α,α-二甲基-4-(α,α,β,β-四氟苯乙基)苄胺（MK-251）的多种代谢产物的鉴定情况。该化合物在犬、猴、狒狒和人体内均被广泛代谢。所有物种的代谢谱相似。通过溶剂萃取和色谱法（柱色谱、气相色谱和薄层色谱）完成分离和纯化。采用气相色谱、衍生化、红外光谱、核磁共振，特别是气相色谱-低分辨率和高分辨率质谱联用技术对代谢产物进行表征。主要的尿液和血浆代谢产物被鉴定为2-[4-(α,α,β,β-四氟苯乙基)苯基]-2-丙醇及其葡萄糖醛酸结合物。鉴定出的其他代谢产物有：MK-251的N-葡萄糖醛酸苷；2-[4-(α,α,β,β-四氟苯乙基)苯基]丙烯；2-硝基-2-[4-(α,α,β,β-四氟苯乙基)苯基]丙烷；α,α-二甲基-4(α,α,β,β-四氟苯乙基)苄基甲基醚；以及4-(α,α,β,β-四氟苯乙基)苯乙酮。0-甲基醚代谢产物代表叔醇体内烷基化的首例情况。对MK-251的N-羟基类似物和2-[4-(α,α,β,β-四氟苯乙基)苯基]-2-丙醇的二醇类似物进行了初步鉴定。观察到的药理反应似乎主要源于MK-251，而非这四种代谢产物。