Shenyang Pharmaceutical University, Shenyang, 110016, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193, China.
Drug Test Anal. 2014 Jun;6(6):552-62. doi: 10.1002/dta.1564. Epub 2013 Dec 6.
Aildenafil, 1-{[3-(6, 7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4, 3-d] primidin-5-yl)-4-ethoxyphenyl] sulfonyl}-cis-3, 5-dimethylpiperazine, a phosphodiesterase type V enzyme inhibitor (PDE5I), is under development for treatment of erectile dysfunction (ED). The purpose of this study was to elucidate metabolism of aildenafil in vivo in rats and in vitro in mouse, rat, dog, and human liver microsomes. Thirty-one phase I metabolites have been found by LTQ/Orbitrap hybrid mass spectrometry in rat urine, faeces, and bile after oral administration. Major biotransformation pathways of aildenafil included N-dealkylation of the piperazine ring, hydroxylation and dehydrogenation, aliphatic hydroxylation and loss of alkyl group of piperazine ring. Minor pathways involved hydroxylation on the phenyl ring, pyrazole N-demethylation, O-deethylation, loss of piperazine ring (cleavage of N-S bond) and dehydrogenation on the piperazine ring. Similar metabolic pathways of aildenafil were observed in the incubations of liver microsomes from mouse, rat, and dog as well as from human. The depletion rate of parent drug in mouse and rat liver microsomes was significantly different from that in human liver microsomes. The cytochrome P450 reaction phenotyping analysis was conducted using isozyme-specific inhibitors. The results indicated that CYP3A was the main isoenzyme involved in oxidative metabolism of aildenafil. Overall, these in vitro and in vivo findings should provide valuable information on possible metabolic behaviours of aildenafil in humans.
阿伐那非，1-[[3-(6,7-二氢-1-甲基-7-氧代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)-4-乙氧基苯基]磺酰基]-顺-3,5-二甲基哌嗪，一种磷酸二酯酶 5 型（PDE5）酶抑制剂，正在开发用于治疗勃起功能障碍（ED）。本研究旨在阐明阿伐那非在大鼠体内和在小鼠、大鼠、狗和人肝微粒体中的代谢情况。在大鼠口服给药后的尿液、粪便和胆汁中，通过 LTQ/Orbitrap 杂交质谱法发现了 31 种 I 相代谢物。阿伐那非的主要生物转化途径包括哌嗪环的 N-脱烷基化、羟化和脱氢、脂肪族羟化和哌嗪环烷基的丢失。次要途径包括苯环的羟化、吡唑 N-去甲基化、O-去乙基化、哌嗪环的丢失（N-S 键的断裂）和哌嗪环的脱氢。在小鼠、大鼠和狗肝微粒体孵育以及人肝微粒体中观察到类似的阿伐那非代谢途径。在小鼠和大鼠肝微粒体中，母体药物的耗竭率与在人肝微粒体中明显不同。使用同工酶特异性抑制剂进行了细胞色素 P450 反应表型分析。结果表明，CYP3A 是参与阿伐那非氧化代谢的主要同工酶。总体而言，这些体内和体外研究结果应为了解阿伐那非在人体内可能的代谢行为提供有价值的信息。
