SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (∼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.

中文翻译：

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5HT6拮抗剂2-甲基-1-（苯基磺酰基）-4-（哌嗪-1-基）-1H-苯并[d]咪唑（SAM-760）的代谢：磺酰胺代谢对酮康唑介导的减量的影响临床药物相互作用。

在人中研究了5HT6拮抗剂SAM-760 [（2-甲基-1-（苯磺酰基）-4-（哌嗪-1-基）-1H-苯并[d]咪唑）]，用于治疗阿尔茨海默氏病。在肝微粒体和重组细胞色素P450（P450）同工酶中，SAM-760主要被CYP3A代谢（〜85％）。根据这些观察结果，并期望与中度至强效CYP3A抑制剂发生5倍相互作用的程度，进行了临床DDI研究。在存在酮康唑的情况下，从零时间外推到SAM-760的无限时间值的血浆浓度-时间曲线下的平均Cmax和面积分别仅适度增加了30％和38％。使用[14C] SAM-760对这种出乎意料的低相互作用进行了体外研究。在人类肝细胞中进行放射线分析，证实了以前用未标记的SAM-760观察到的所有氧化代谢产物；但是，主要的辐射峰是意外的极性代谢产物，对pan-P450抑制剂1-氨基苯并三唑不敏感。在人类肝细胞中，放射整合将SAM-760总代谢的43％归因于这种非P450途径。使用真实的标准品，确认该主要代谢物为苯亚磺酸。进一步的研究表明，苯亚磺酸代谢产物可能是SAM-760芳基磺酰胺基团的一种新型的，非酶促的，巯基介导的还原性裂解。我们还通过在存在和不存在P450异构体特异性抑制剂的情况下，通过追踪氧化代谢产物的形成速度，来确定P450对人肝细胞中SAM-760代谢的相对贡献。P450介导的SAM-760氧化代谢仍主要归因于CYP3A（33％），P450亚型CYP2C19和CYP2D6的贡献很小。因此，当SAM-760与酮康唑合用时，通过新型磺酰胺代谢和CYP3A在人肝细胞中的[14C] SAM-760处置证明低于预期的临床DDI。