Abstract

1. The purpose of this study was to investigate the pharmacokinetic behaviour of mirogabalin in rats and monkeys.

2. Pharmacokinetic parameters of mirogabalin after its oral and intravenous administration were determined. Distribution study, mass balance study, and metabolite identification were also conducted after the oral administration of [¹⁴C]mirogabalin.

3. Plasma exposure (C_max and AUC_inf) increased dose-proportionally after the oral administration of mirogabalin at 1, 3, and 10 mg/kg to rats and monkeys. Mean total body clearance (CL_tot) after intravenous administration at 3 mg/kg was 13.5 mL/min/kg in rats and 9.02 mL/min/kg in monkeys, and absolute bioavailability at 3 mg/kg was 97.6% in rats and 85.2% in monkeys. There was a greater recovery of radioactivity in urine than that in faeces after the oral administration of [¹⁴C]mirogabalin. The main radioactive component in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), an oxidised metabolite of mirogabalin, mirogabalin N-glucuronide and O-glucuronide of oxidised A204-4455 were detected as minor components in monkeys and rats.

4. Mirogabalin administered orally was almost completely eliminated via urinary excretion. A small part of the orally administered dose of mirogabalin was metabolised via glucuronidation at the amine and carboxylic acid moiety and oxidation as the primary metabolic pathway.

摘要

1. 本研究的目的是研究米洛巴林在大鼠和猴子体内的药代动力学行为。

2. 测定米洛巴林口服和静脉给药后的药代动力学参数。在口服[ ¹⁴ C]米罗加巴林后还进行了分布研究、质量平衡研究和代谢物鉴定。

3. 大鼠和猴子口服米洛巴林 1、3 和 10 mg/kg 后，血浆暴露量（C _max和 AUC _{inf ）按剂量比例增加。}3 mg/kg 静脉给药后的平均全身清除率 (CL _tot ) 大鼠为 13.5 mL/min/kg，猴为 9.02 mL/min/kg，3 mg/kg 大鼠的绝对生物利用度为 97.6%，大鼠为 85.2% % 在猴子身上。口服[ ¹⁴ C]米罗加巴林后，尿液中放射性的恢复大于粪便中的放射性。血浆、尿液和粪便中的主要放射性成分是米洛巴林。A204-4455（内酰胺形式），米洛加巴林、米加巴林N-葡糖苷酸和O的氧化代谢物在猴子和大鼠中检测到氧化的 A204-4455 的葡萄糖苷酸为微量成分。

4. 口服米罗巴林几乎完全通过尿排泄消除。米洛巴林口服剂量的一小部分通过胺和羧酸部分的葡萄糖醛酸化和氧化作为主要代谢途径进行代谢。