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

作　　者：Yi-fei He Yin Liu Jing-hua Yu Huan Cheng Abdullajon Odilov Fei-pu Yang Guang-hui Tian Xiu-mei Yao Hua-qing Duan Cheng-yin Yu Chen Yu Yan-mei Liu Gang-yi Liu Jing-shan Shen Zhen Wang Xing-xing Diao 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2023年第1期221-233,共13页中国药理学报（英文版）

基　　金：The research was sponsored by Vigonvita Life Sciences Co.,Ltd and was partially financially supported by a grant from the National Natural Science Foundation of China(No.81903701).

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[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(100μCi)of[14C]TPN171.We found that TPN171 was absorbed rapidly in humans with a peak time(T_(max))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 P4503A4(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.

关 键 词：TPN171 [14C]TPN171 PDE5 inhibitor pulmonary arterial hypertension healthy volunteers PHARMACOKINETICS metaboliteidentification mass balance 

分 类 号：O62[理学—有机化学]