Pharmacokinetics, mass balance, and metabolism of [14C] TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension

Yi-fei He1,2, Yin Liu1,2, Jing-hua Yu1, Huan Cheng1,3, Abdullajon Odilov1,2, Fei-pu Yang1, Guang-hui Tian4, Xiu-mei Yao4, Hua-qing Duan4, Cheng-yin Yu5, Chen Yu5, Yan-mei Liu5, Gang-yi Liu5, Jing-shan Shen1,2, Zhen Wang1,6, Xing-xing Diao1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of the Chinese Academy of Sciences, Beijing 100049, China
3 School of Pharmaceutical Sciences, Shandong University of Traditional Chinese Medicine, Ji-nan 250355, China
4 Vigonvita Life Sciences Co., Ltd, Suzhou 215000, China
5 Shanghai Xuhui Central Hospital, Shanghai 200030, China
6 Lingang Laboratory, Shanghai 201602, China
Correspondence to: Zhen Wang:, Xing-xing Diao:,
DOI: 10.1038/s41401-022-00922-6
Received: 31 December 2021
Accepted: 11 May 2022
Advance online: 8 June 2022


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 [14C]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 μCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) 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.
Keywords: TPN171; [14C]TPN171; PDE5 inhibitor; pulmonary arterial hypertension; healthy volunteers; pharmacokinetics; metabolite identification; mass balance

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