Tomori E, Horváth G, Pátfalusi M, Mészáros S, Vereczkey L
Institute for Drug Research, Budapest, Hungary.
J Chromatogr. 1992 Jul 1;578(1):91-101. doi: 10.1016/0378-4347(92)80229-j.
Girisopam possesses selective anxiolytic action without muscle relaxant and anticonvulsive activity. After a 100-mg oral dose of 14C-labelled girisopam to seven male subjects, the mean recovery of 14C radioactivity was 51% in urine and 33% in faeces. A high-performance liquid chromatographic method has been developed for studying girisopam in single-dose pharmacokinetic studies. The serum extract was chromatographed on a normal-phase column using a mobile phase of hexane-ethanol-diethyl ether (66:9:25, v/v) and ultraviolet detection at 235 nm. The recovery was 60% and the detection limit was 3 ng/ml, using 1 ml of serum. After a 20-min delay, girisopam is rapidly absorbed. After reaching a mean serum level of 178 ng/ml at a mean time of 2.0 h, the serum concentration of girisopam decreased with a mean elimination half-time of 22.2 h. The metabolites were separated by high-performance liquid chromatography, radio thin-layer chromatography and gas chromatography. Their structures were determined by liquid chromatography-mass spectrometry, mass spectrometry and gas chromatography-mass spectrometry. Their chemical structures were confirmed by comparison with synthesized reference compounds. The major urinary metabolites were 7-demethylgirisopam (I), 4'-hydroxygirisopam (II) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in conjugated form, and 4-carboxy-4-demethylgirisopam (V), a compound with an open-chain structure (VII) and traces of 4-demethyl-4-oxogirisopam (VIII) and 4-hydroxymethyl-4-demethylgirisopam (III), which were in non-conjugated form. The metabolic profile in the serum consisted predominantly of the glucuronides of I, II and III. The non-conjugated metabolites were the metabolite with the open-chain structure (VII), III and V. Besides the parent compound, the faeces sample contained conjugates of I and II.
吉立索泮具有选择性抗焦虑作用，而无肌肉松弛和抗惊厥活性。给7名男性受试者口服100mg 14C标记的吉立索泮后，尿中14C放射性的平均回收率为51%，粪便中为33%。已开发出一种高效液相色谱法用于单剂量药代动力学研究中对吉立索泮的研究。血清提取物在正相柱上进行色谱分离，流动相为己烷 - 乙醇 - 乙醚（66:9:25，v/v），在235nm处进行紫外检测。使用1ml血清时，回收率为60%，检测限为3ng/ml。延迟20分钟后，吉立索泮迅速吸收。在平均时间2.0小时达到平均血清水平178ng/ml后，吉立索泮的血清浓度下降，平均消除半衰期为22.2小时。代谢产物通过高效液相色谱、放射性薄层色谱和气相色谱进行分离。它们的结构通过液相色谱 - 质谱、质谱和气相色谱 - 质谱测定。通过与合成参考化合物比较确认了它们的化学结构。主要的尿代谢产物为7 - 去甲基吉立索泮（I）、4'-羟基吉立索泮（II）和4 - 羟甲基 - 4 - 去甲基吉立索泮（III），它们以结合形式存在，以及4 - 羧基 - 4 - 去甲基吉立索泮（V），一种具有开链结构的化合物（VII）和痕量的4 - 去甲基 - 4 - 氧代吉立索泮（VIII）和4 - 羟甲基 - 4 - 去甲基吉立索泮（III），它们以非结合形式存在。血清中的代谢谱主要由I、II和III的葡糖醛酸苷组成。非结合代谢产物为具有开链结构的代谢产物（VII）、III和V。除母体化合物外，粪便样品中含有I和II的结合物。
