Pharmacokinetics, mass balance, and metabolism of [C-14]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension
文献类型：期刊论文
| 作者 | He, Yi-fei5,6; Liu, Yin5,6; Yu, Jing-hua6; Cheng, Huan4,6; Odilov, Abdullajon5,6; Yang, Fei-pu6; Tian, Guang-hui3; Yao, Xiu-mei3; Duan, Hua-qing3; Yu, Cheng-yin2 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2022-06-08 |
| 页码 | 13 |
| 关键词 | TPN171 [C-14]TPN171 PDE5 inhibitor pulmonary arterial hypertension healthy volunteers pharmacokinetics metabolite identification mass balance |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-022-00922-6 |
| 通讯作者 | Wang, Zhen(wangzhen@lglab.ac.cn) ; Diao, Xing-xing(xxdiao@simm.ac.cn) |
| 英文摘要 | TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [C-14]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 mu Ci) of [C-14]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (T-max) of 0.667 h and a half-life (t(1/2)) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10. |
| WOS关键词 | UDP-GLUCURONOSYLTRANSFERASES ; LIVER-MICROSOMES ; MESSENGER-RNA ; PHASE-I ; SAFETY ; CYTOCHROME-P450 ; EXPRESSION ; EXCRETION ; GLUCURONIDATION ; TOLERABILITY |
| 资助项目 | Vigonvita Life Sciences Co., Ltd ; National Natural Science Foundation of China[81903701] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000807946700001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/301355]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Wang, Zhen; Diao, Xing-xing |
| 作者单位 | 1.Lingang Lab, Shanghai 201602, Peoples R China 2.Shanghai Xuhui Cent Hosp, Shanghai 200030, Peoples R China 3.Vigonvita Life Sci Co Ltd, Suzhou 215000, Peoples R China 4.Shandong Univ Tradit Chinese Med, Sch Pharmaceut Sci, Jinan 250355, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | He, Yi-fei,Liu, Yin,Yu, Jing-hua,et al. Pharmacokinetics, mass balance, and metabolism of [C-14]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension[J]. ACTA PHARMACOLOGICA SINICA,2022:13. |
| APA | He, Yi-fei.,Liu, Yin.,Yu, Jing-hua.,Cheng, Huan.,Odilov, Abdullajon.,...&Diao, Xing-xing.(2022).Pharmacokinetics, mass balance, and metabolism of [C-14]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.ACTA PHARMACOLOGICA SINICA,13. |
| MLA | He, Yi-fei,et al."Pharmacokinetics, mass balance, and metabolism of [C-14]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension".ACTA PHARMACOLOGICA SINICA (2022):13. |
入库方式： OAI收割
来源：上海药物研究所
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