Species differences in the CYP3A-catalyzed metabolism of TPN729, a novel PDE5 inhibitor
| Autor: | Xianglei Zhang, Yechun Xu, Y. L. Zhu, Zhen Wang, Xiangrui Jiang, Jingshan Shen, Xingxing Diao, Dafang Zhong, Qian-Qian Tian |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine CYP3A Metabolite Pyrimidinones Plasma protein binding Pharmacology Mass Spectrometry Article Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Dogs 0302 clinical medicine Species Specificity Pharmacokinetics Animals Cytochrome P-450 CYP3A Humans Pharmacology (medical) Chromatography High Pressure Liquid Active metabolite Sulfonamides CYP3A4 General Medicine Metabolism Phosphodiesterase 5 Inhibitors Macaca fascicularis 030104 developmental biology chemistry 030220 oncology & carcinogenesis cGMP-specific phosphodiesterase type 5 Microsomes Liver |
| Zdroj: | Acta Pharmacol Sin |
| ISSN: | 1745-7254 1671-4083 |
| DOI: | 10.1038/s41401-020-0447-x |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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