Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor

doi:10.1038/s41401-020-0447-x

	Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor
	Tian, Qian-qian 1,2; Zhu, Yun-ting 1,2; Diao, Xing-xing 2; Zhang, Xiang-lei 2; Xu, Ye-chun 2; Jiang, Xiang-rui 3; Shen, Jing-shan 3; Wang, Zhen 3; Zhong, Da-fang 1,2
刊名	ACTA PHARMACOLOGICA SINICA
	2020-06-24
页码	9
关键词	PDE5 inhibitor TPN729 M3 species difference pharmacokinetics metabolite identification
ISSN号	1671-4083
DOI	10.1038/s41401-020-0447-x
通讯作者	Wang, Zhen(wangzhen@simm.ac.cn) ; Zhong, Da-fang(dfzhong@simm.ac.cn)
英文摘要	TPN729 is a novel phosphodiesterase 5 (PDE5) inhibitor used to treat erectile dysfunction in men. Our previous study shows that the plasma exposure of metabolite M3 (N-dealkylation of TPN729) in humans is much higher than that of TPN729. In this study, we compared its metabolism and pharmacokinetics in different species and explored the contribution of its main metabolite M3 to pharmacological effect. We conducted a combinatory approach of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry-based metabolite identification, and examined pharmacokinetic profiles in monkeys, dogs, and rats following TPN729 administration. A remarkable species difference was observed in the relative abundance of major metabolite M3: i.e., the plasma exposure of M3 was 7.6-fold higher than that of TPN729 in humans, and 3.5-, 1.2-, 1.1-fold in monkeys, dogs, and rats, respectively. We incubated liver S9 and liver microsomes with TPN729 and CYP3A inhibitors, and demonstrated that CYP3A was responsible for TPN729 metabolism and M3 formation in humans. The inhibitory activity of M3 on PDE5 was 0.78-fold that of TPN729 (The IC(50)values of TPN729 and M3 for PDE5A were 6.17 +/- 0.48 and 7.94 +/- 0.07 nM, respectively.). The plasma protein binding rates of TPN729 and M3 in humans were 92.7% and 98.7%, respectively. It was astonishing that the catalyzing capability of CYP3A4 in M3 formation exhibited seven-fold disparity between different species. M3 was an active metabolite, and its pharmacological contribution was equal to that of TPN729 in humans. These findings provide new insights into the limitation and selection of animal model for predicting the clinical pharmacokinetics of drug candidates metabolized by CYP3A4.
资助项目	National Natural Science Foundation of China[81521005] ; National Natural Science Foundation of China[81903701] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306]
WOS关键词	IN-VITRO METABOLISM ; LIVER-MICROSOMES ; CYTOCHROME-P450 3A4 ; DRUG-METABOLISM ; PHARMACOKINETICS ; SILDENAFIL ; MOUSE ; RAT ; DOG ; MONKEY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000543023900001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291743]
专题	中国科学院上海药物研究所
通讯作者	Wang, Zhen; Zhong, Da-fang
作者单位	1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Tian, Qian-qian,Zhu, Yun-ting,Diao, Xing-xing,et al. Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor[J]. ACTA PHARMACOLOGICA SINICA,2020:9.
APA	Tian, Qian-qian.,Zhu, Yun-ting.,Diao, Xing-xing.,Zhang, Xiang-lei.,Xu, Ye-chun.,...&Zhong, Da-fang.(2020).Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor.ACTA PHARMACOLOGICA SINICA,9.
MLA	Tian, Qian-qian,et al."Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor".ACTA PHARMACOLOGICA SINICA (2020):9.