Amore Benny M, Cramer Clay, MacDougall Diane, Emery Maurice G
Esperion Therapeutics, Inc., Ann Arbor, Michigan
Esperion Therapeutics, Inc., Ann Arbor, Michigan.
Drug Metab Dispos. 2023 May;51(5):599-609. doi: 10.1124/dmd.122.001142. Epub 2023 Mar 6.
The disposition and metabolism of bempedoic acid, a selective inhibitor of ATP citrate lyase, were examined in healthy male subjects. After a single administration of [C] bempedoic acid (240 mg, 113 Ci) oral solution, mean concentrations of total radioactivity in plasma as a function of time indicated absorption was rapid with peak concentrations achieved at 1 hour after dose administration. Radioactivity was decreased in a multiexponential fashion with an estimated elimination half-life of 26.0 hours. Radiolabeled dose was predominantly recovered in urine (62.1% of dose) and a smaller amount in feces (25.4% of dose). Bempedoic acid was extensively metabolized with 1.6%-3.7% of dose excreted unchanged in urine and feces combined. Overall, the major clearance route of bempedoic acid is metabolism by uridine 5'-diphosphate glucuronosyltransferases. Metabolism in hepatocyte cultures of human and nonclinical species were generally in agreement with clinical metabolite profiles. Pooled plasma samples were characterized by the presence of bempedoic acid (ETC-1002), which accounted for 59.3% of total plasma radioactivity, ESP15228 (M7; a reversible keto metabolite of bempedoic acid), and their respective glucuronide conjugates. The acyl glucuronide of bempedoic acid (M6) represented 23%-36% of radioactivity in plasma and accounted for approximately 37% of dose excreted in urine. In feces, the majority of radioactivity was associated with a co-eluting mixture of a carboxylic acid metabolite of bempedoic acid (M2a), a taurine conjugate of bempedoic acid (M2c), and hydroxymethyl-ESP15228 (M2b), which collectively accounted for 3.1%-22.9% of bempedoic acid dose across subjects. SIGNIFICANCE STATEMENT: This study characterizes the disposition and metabolism of bempedoic acid, an inhibitor of ATP citrate lyase for hypercholesterolemia. This work provides further understanding of bempedoic acid clinical pharmacokinetics and clearance pathways in adult subjects.
在健康男性受试者中研究了ATP柠檬酸裂解酶的选择性抑制剂贝派地酸的处置和代谢情况。单次口服给予[C]贝派地酸（240mg，113Ci）溶液后，血浆中总放射性的平均浓度随时间变化表明吸收迅速，给药后1小时达到峰值浓度。放射性以多指数方式下降，估计消除半衰期为26.0小时。放射性标记剂量主要在尿液中回收（占剂量的62.1%），在粪便中回收量较少（占剂量的25.4%）。贝派地酸被广泛代谢，尿液和粪便中未变化排泄的剂量占1.6%-3.7%。总体而言，贝派地酸的主要清除途径是通过尿苷5'-二磷酸葡萄糖醛酸转移酶进行代谢。人和非临床物种肝细胞培养中的代谢情况与临床代谢物谱总体一致。合并血浆样本的特征是存在贝派地酸（ETC-1002），其占血浆总放射性的59.3%，ESP15228（M7；贝派地酸的可逆酮代谢物）及其各自的葡萄糖醛酸共轭物。贝派地酸的酰基葡萄糖醛酸（M6）占血浆放射性的23%-36%，约占尿液中排泄剂量的37%。在粪便中，大部分放射性与贝派地酸羧酸代谢物（M2a）、贝派地酸牛磺酸共轭物（M2c）和羟甲基-ESP15228（M2b）的共洗脱混合物相关，这些物质在各受试者中占贝派地酸剂量的3.1%-22.9%。意义声明：本研究描述了用于治疗高胆固醇血症的ATP柠檬酸裂解酶抑制剂贝派地酸的处置和代谢情况。这项工作进一步加深了对成年受试者中贝派地酸临床药代动力学和清除途径的理解。
