Spero Therapeutics, Inc., Cambridge, Massachusetts, USA.
Maier Metrics and Associates LLC, Worcester, Massachusetts, USA.
Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0150922. doi: 10.1128/aac.01509-22. Epub 2023 Mar 30.
Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral prodrug of pharmacologically active moiety tebipenem (TBP), which is a carbapenem with activity against multidrug-resistant Gram-negative pathogens. Conversion from the prodrug to the active moiety, namely, TBP, occurs in the enterocytes of the gastrointestinal tract via intestinal esterases. The absorption, metabolism, and excretion in humans were evaluated, following the administration of a single oral dose of [C]-TBP-PI-HBr. Healthy male subjects ( = 8) received a single 600 mg oral dose of TBP-PI-HBr containing approximately 150 μCi of [C]-TBP-PI-HBr. Blood, urine, and fecal samples were collected to determine the total radioactivity, concentrations of TBP (plasma only), and metabolite profiling and identification. The overall mean recovery of the total radioactivity in urine (38.7%) and feces (44.6%) combined was approximately 83.3% of the administered dose, with individual recoveries ranging from 80.1% to 85.0%. Plasma TBP LC-MS/MS and metabolite profiling data suggest that TBP was the main circulating component in plasma and that it accounts for approximately 54% of the total plasma radioactivity, based on the plasma AUC ratio of TBP/total radioactivity. The ring-open metabolite LJC 11562 was another major component in plasma (>10%). TBP (M12), LJC 11562, and four trace to minor metabolites were identified/characterized in the urine. TBP-PI, TBP (M12), and 11 trace to minor metabolites were identified/characterized in the feces. The renal and fecal routes are major clearance pathways in the elimination of [C]-TBP-PI-HBr, with a mean combined recovery of 83.3%. TBP and its inactive ring-open metabolite LJC 11562 were the major circulating metabolites in the plasma.
盐酸替比培南匹伏酯（TBP-PI-HBr）是一种具有药理活性的替比培南（TBP）的口服前药，替比培南是一种对多种耐药革兰氏阴性病原体具有活性的碳青霉烯类抗生素。该前药通过胃肠道的肠酯酶在肠细胞中转化为活性部分 TBP。在给予单剂量口服[C]-TBP-PI-HBr 后，评估了 TBP-PI-HBr 在人体内的吸收、代谢和排泄。8 名健康男性受试者接受了单剂量 600mg 口服 TBP-PI-HBr 剂量，其中含有约 150μCi 的[C]-TBP-PI-HBr。采集血、尿和粪便样本以确定总放射性、TBP 浓度（仅在血浆中）以及代谢产物谱分析和鉴定。尿（38.7%）和粪便（44.6%）中总放射性的总回收率约为给药剂量的 83.3%，个体回收率范围为 80.1%至 85.0%。TBP 的 LC-MS/MS 和代谢产物谱数据表明，TBP 是血浆中的主要循环成分，根据 TBP/总放射性的血浆 AUC 比值，它占总血浆放射性的约 54%。开环代谢物 LJC 11562 也是血浆中的主要成分（>10%）。在尿液中鉴定/表征了 TBP（M12）、LJC 11562 和四种痕量至微量代谢物。在粪便中鉴定/表征了 TBP-PI、TBP（M12）和 11 种痕量至微量代谢物。肾脏和粪便途径是消除[C]-TBP-PI-HBr 的主要清除途径，总回收率平均值为 83.3%。TBP 和其无活性的开环代谢物 LJC 11562 是血浆中的主要循环代谢物。
