Mutlib A E, Jurcak J, Hrib N
Neuroscience Product Group Unit, Hoechst-Roussel Pharmaceuticals, Inc.
Drug Metab Dispos. 1996 Oct;24(10):1139-50.
Metabolism of an atypical antipsychotic agent, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone (HP236) by rats is described. HP236 was extensively metabolized both in vitro and in vivo. Metabolites were identified using electrospray interface-LC/MS (ESI-LC/MS) and 1H NMR spectroscopy. Protonated molecular ions, MH+, were observed for all the metabolites of HP236 using ESI-LC/MS. Tandem MS was performed on these quasimolecular ions to provide structural information. Structures of metabolites were confirmed by chromatographic and spectroscopic comparisons to synthetic standards. Metabolic pathways for HP236 both in vivo and in vitro included: a) cleavage of the thiazolidinone ring structure to give N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide, N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, and N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]butyl]-acetamide; b) oxidation of the sulfide to give a mixture of sulfoxide diastereoisomers, 3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-1-oxo-2, 5,5-trimethyl-4-thiazolidinone and a sulfone, 1,1-dioxo-3-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl ]-2, 5,5-trimethyl-4-thiazolidinone; and c) N-dealkylation at the piperazine ring to produce 3-(4-(1-piperazinyl]butyl]-2, 5,5-trimethyl-4-thiazolidinone and 6-fluoro-3-(1-piperazinyl)benzo[b]thiophene. Metabolites found circulating in the plasma of rats dosed with HP236 were identical to those produced in vitro using rat liver microsomes or S9 fractions; however, LC/MS analysis of rat urine extract showed that the metabolite profile was different than that obtained from plasma or from in vitro extracts. The metabolite resulting from the cleavage of the thiazolidinone ring, N-acetyl-N-[4-[4-(6-fluorobenzo[b] thien-3-yl)-1-piperazinyl]-butyl]-2-methyl-propanamide, was the major circulating metabolite in the plasma of rats dosed with HP236. Results from in vitro studies showed that the metabolite was also produced by incubating the sulfoxides and sulfone analogs of HP236 with rat liver microsomes. A mechanism for the formation of N-acetyl-N-[4-[4-(6-fluorobenzo [b]thien-3-yl)-1-piperazinyl]butyl]-2-methyl-propanamide from HP236 is proposed.
本文描述了大鼠对一种非典型抗精神病药物3-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2,5,5-三甲基-4-噻唑烷酮（HP236）的代谢情况。HP236在体外和体内均被广泛代谢。使用电喷雾接口-液相色谱/质谱联用仪（ESI-LC/MS）和1H核磁共振光谱对代谢产物进行了鉴定。通过ESI-LC/MS观察到HP236所有代谢产物的质子化分子离子MH+。对这些准分子离子进行串联质谱分析以提供结构信息。通过与合成标准品进行色谱和光谱比较，确认了代谢产物的结构。HP236在体内和体外的代谢途径包括：a）噻唑烷酮环结构裂解，生成N-乙酰基-N-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2-甲基丙酰胺、N-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2-甲基丙酰胺和N-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]乙酰胺；b）硫化物氧化，生成亚砜非对映异构体混合物3-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-1-氧代-2,5,5-三甲基-4-噻唑烷酮和砜1,1-二氧代-3-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2,5,5-三甲基-4-噻唑烷酮；c）哌嗪环上的N-脱烷基化，生成3-(4-(1-哌嗪基]丁基]-2,5,5-三甲基-4-噻唑烷酮和6-氟-3-(1-哌嗪基)苯并[b]噻吩。在给予HP236的大鼠血浆中循环的代谢产物与使用大鼠肝微粒体或S9组分体外产生的代谢产物相同；然而，大鼠尿液提取物的LC/MS分析表明，代谢产物谱与从血浆或体外提取物中获得的不同。噻唑烷酮环裂解产生的代谢产物N-乙酰基-N-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2-甲基丙酰胺是给予HP236的大鼠血浆中的主要循环代谢产物。体外研究结果表明，该代谢产物也可通过将HP236的亚砜和砜类似物与大鼠肝微粒体孵育产生。本文提出了从HP236形成N-乙酰基-N-[4-[4-(6-氟苯并[b]噻吩-3-基)-1-哌嗪基]丁基]-2-甲基丙酰胺的机制。
