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-（苯磺酰基）-4-（哌嗪-1-基）-1H-苯并[d]咪唑 （SAM-760） 的代谢：磺胺代谢对酮康唑介导的临床药物相互作用减少的影响。


SAM-760 [（2-甲基-1-（苯磺酰基）-4-（哌嗪-1-基）-1H-苯并[d]咪唑）]是一种 5HT6 拮抗剂，在人体中用于治疗阿尔茨海默病的研究。在肝微粒体和重组细胞色素 P450 （P450） 同工酶中，SAM-760 主要由 CYP3A 代谢 （∼85%）。基于这些观察结果以及与中度至强 CYP3A 抑制剂相互作用 5 倍量级的预期，进行了一项临床 DDI 研究。在酮康唑存在下，从时间零外推到 SAM-760 的无限时间值的血浆浓度 - 时间曲线下的平均 Cmax 和面积分别仅显示 30% 和 38% 的适度增加。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。人肝细胞中的辐射分析证实了先前使用未标记的 SAM-760 观察到的所有氧化代谢物;然而，主要的放射性峰是一种意外的极性代谢物，它对 pan-P450 抑制剂 1-氨基苯并三唑不敏感。在人肝细胞中，辐射整合将 SAM-760 总代谢的 43% 归因于这种非 P450 途径。使用确证标准品，确认该主要代谢物为苯亚磺酸。进一步的研究表明，苯亚磺酸代谢物可能是 SAM-760 的芳基磺酰胺基团的新型、非酶促的、硫醇介导的还原裂解。我们还通过在存在和不存在 P450 亚型特异性抑制剂的情况下跟踪氧化代谢物的形成速率，确定了 P450 对人肝细胞中 SAM-760 代谢的相对贡献。 P450 介导的 SAM-760 氧化代谢仍然主要归因于 CYP3A （33%），P450 亚型 CYP2C19 和 CYP2D6 的贡献很小。因此，当 SAM-760 与酮康唑联合给药时，[14C]SAM-760 通过新型磺酰胺代谢和 CYP3A 在人肝细胞中的处置验证了低于预期的临床 DDI。