Toque Haroldo A, Teixeira Cleber E, Lorenzetti Raquel, Okuyama Cristina E, Antunes Edson, De Nucci Gilberto
Department of Pharmacology, UNICAMP, Campinas, SP, 13081-970, Brazil.
Eur J Pharmacol. 2008 Sep 4;591(1-3):189-95. doi: 10.1016/j.ejphar.2008.06.055. Epub 2008 Jun 19.
Nitrergic nerves and endothelial cells release nitric oxide (NO) in the corpus cavernosum, a key mediator that stimulates soluble guanylyl cyclase to increase cGMP levels causing penile erection. Phosphodiesterase 5 (PDE5) inhibitors, such as sildenafil, prolong the NO effects by inhibiting cGMP breakdown. Here, we report a novel PDE5 inhibitor, lodenafil carbonate, (Bis-(2-{4-[4-ethoxy-3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-benzenesulfonyl]piperazin-1-yl}-ethyl)carbonate) that is a dimer of lodenafil. We therefore aimed to compare the effects of sildenafil, lodenafil and lodenafil carbonate on in vitro human and rabbit cavernosal relaxations, activity of crude PDE extracts from human platelets, as well as stability and metabolic studies in rat, dog and human plasma. Pharmacokinetic evaluations after intravenous and oral administration were performed in male beagles. Functional experiments were conducted using organ bath techniques. Pharmacokinetics was studied in beagles by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), following oral or intravascular administration. All PDE5 inhibitors tested concentration-dependently relaxed (0.001-100 microM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 microM) or electrical field stimulation (EFS, 1-20 Hz) were markedly potentiated by sildenafil, lodenafil and lodenafil carbonate. Lodenafil carbonate was more potent to inhibit the cGMP hydrolysis in PDE extracts compared with lodenafil and sildenafil. Following intravascular and single oral administration of lodenafil carbonate, only lodenafil and norlodenafil were detected in vivo. These results indicate that lodenafil carbonate works as a prodrug, being lodenafil the active moiety of lodenafil carbonate.
一氧化氮能神经和内皮细胞在阴茎海绵体内释放一氧化氮（NO），NO是一种关键介质，可刺激可溶性鸟苷酸环化酶增加环磷酸鸟苷（cGMP）水平，从而导致阴茎勃起。磷酸二酯酶5（PDE5）抑制剂，如西地那非，通过抑制cGMP分解来延长NO的作用。在此，我们报告一种新型PDE5抑制剂——洛地那非碳酸酯（双-(2-{4-[4-乙氧基-3-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)-苯磺酰基]哌嗪-1-基}-乙基)碳酸酯），它是洛地那非的二聚体。因此，我们旨在比较西地那非、洛地那非和洛地那非碳酸酯对体外人及兔海绵体舒张、人血小板粗提物中PDE活性的影响，以及在大鼠、犬和人血浆中的稳定性和代谢研究。对雄性比格犬进行静脉和口服给药后的药代动力学评估。使用器官浴技术进行功能实验。通过液相色谱-串联质谱联用（LC-MS/MS）研究比格犬口服或血管内给药后的药代动力学。所有测试的PDE5抑制剂均以浓度依赖性方式舒张（0.001 - 100 microM）去氧肾上腺素预收缩的兔和人阴茎海绵体。西地那非、洛地那非和洛地那非碳酸酯显著增强了由乙酰胆碱（0.01 - 100 microM）或电场刺激（EFS，1 - 20 Hz）引起的海绵体舒张。与洛地那非和西地那非相比，洛地那非碳酸酯在抑制PDE提取物中cGMP水解方面更有效。在血管内和单次口服洛地那非碳酸酯后，体内仅检测到洛地那非和去甲洛地那非。这些结果表明，洛地那非碳酸酯作为前药起作用，洛地那非是洛地那非碳酸酯的活性部分。
