PK Sciences, Novartis Institute for Biomedical Research, Novartis Pharma, Basel, Switzerland.
Biopharm Drug Dispos. 2020 Apr;41(4-5):166-183. doi: 10.1002/bdd.2226. Epub 2020 Apr 7.
EMA401, (the S-enantiomer of 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), also known as Olodanrigan, is an orally active selective angiotensin II type 2 receptor (AT R) antagonist that is in Phase IIb clinical development as a novel analgesic for the relief of chronic pain. The main purpose of the present work was to investigate the disposition of a single C- labeled EMA401 in non-clinical studies. The in vitro metabolism studies of EMA401 were undertaken to understand the hepatic biotransformation pathways in animal species used in toxicology studies and how they compare to human. Furthermore, investigation of EMA401's PK was carried out in vivo in rats. The study demonstrates the rapid absorption and distribution of drug-related material mainly to the tissues associated with absorption and elimination (GI tract, liver, and kidney). EMA401was then readily eliminated metabolically via the bile (95% of dose) predominantly in the form of the direct acylglucuronide (40% of dose), which was further hydrolysed by the intestinal flora to the active parent drug. Other metabolic pathways such as dealkylations and hydroxylation were also involved in the elimination of EMA401 to a lesser extent. EMA401 was metabolically unstable in hepatocytes of all species investigated and the key metabolites produced in the in vitro model were also detected in vivo. Independent of the dosing route, the S-enantiomer EMA401 showed a good in vivo chiral stability. Overall, the present study provides the first full characterization of the disposition of EMA401 in preclinical species.
EMA401（5-(苯甲氧基)-2-(2,2-二苯基乙酰基)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸的 S-对映异构体），也称为 Olodanrigan，是一种口服活性的选择性血管紧张素 II 型 2 型受体（AT R）拮抗剂，目前处于 IIb 期临床开发阶段，作为一种新型镇痛药用于缓解慢性疼痛。本工作的主要目的是研究单次 C-标记 EMA401 在非临床研究中的处置情况。进行了 EMA401 的体外代谢研究，以了解毒理学研究中使用的动物物种中的肝生物转化途径，以及它们与人类的比较。此外，还在大鼠体内进行了 EMA401 的 PK 研究。该研究表明，药物相关物质主要通过吸收和消除（胃肠道、肝脏和肾脏）相关组织快速吸收和分布。然后，EMA401 通过胆汁（95%的剂量）主要以直接酰基葡萄糖醛酸苷（40%的剂量）的形式迅速代谢消除，该物质进一步被肠道菌群水解为活性母体药物。其他代谢途径，如脱烷基化和羟化，也在 EMA401 的消除中起次要作用。EMA401 在所有研究的种属的肝细胞中代谢不稳定，并且在体外模型中产生的关键代谢物也在体内检测到。无论给药途径如何，S-对映异构体 EMA401 在体内均表现出良好的手性稳定性。总体而言，本研究首次全面描述了 EMA401 在临床前种属中的处置情况。
