Tadalafil is an effective, reversible and selective small molecule inhibitor of phosphodiesterase 5 (PDE5) with an IC50 of 1.8nM. Tadalafil can also inhibit PDE11 (IC50 of 11nM) [1-2]. PDE is a key protein that regulates intracellular cyclic nucleotide turnover and smooth muscle tension [3]. Tadalafil can be used to treat erectile dysfunction and improve pulmonary arterial hypertension [4].
In vitro, different concentrations of Tadalafil (0.2, 0.1, 0.05 and 0.025μg/ml; 0.5ml; 2h) were applied to semen samples collected from normal human sperm groups and weak sperm groups. At a concentration of 0.025μg/ml, sperm motility significantly increased [5]. Tadalafil (1, 3 and 10μM; 48h) increased the expression of CYP3A protein in human liver cells, while the CYP3A activity did not increase accordingly [6].
In vivo, Tadalafil (0.09mg/200g body weight/day; gavage; 2 months) significantly improved erectile function in streptozotocin-induced diabetic rats, increased the percentage of smooth muscle and elastic tissue area, and significantly reduced fibrous tissue [7]. Tadalafil (1mg/kg/day; 4 weeks; i.p.) treatment alleviated cardiac hypertrophy and pulmonary edema in mice with myocardial infarction (MI), reduced the area of fibrosis and decreased cell apoptosis [8].
References:
[1] Blount MA, Beasley A, Zoraghi R, et al. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol. 2004;66(1):144-152.
[2] Card, G.L., England, B.P., Suzuki, Y., et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 12(12), 2233-2247 (2004).
[3] Gratzke C, Ückert S, Kedia G, et al. In vitro effects of PDE5 inhibitors sildenafil, vardenafil and tadalafil on isolated human ureteral smooth muscle: a basic research approach[J]. Urological research, 2007, 35(1): 49-54.
[4] Coward R M, Carson C C. Tadalafil in the treatment of erectile dysfunction[J]. Therapeutics and clinical risk management, 2008, 4(6): 1315-1330.
[5] Yang Y, Ma Y, Yang H, et al. Effect of acute tadalafil on sperm motility and acrosome reaction: in vitro and in vivo studies. Andrologia. 2014;46(4):417-422.
[6] Ring B J, Patterson B E, Mitchell M I, et al. Effect of tadalafil on cytochrome P450 3A4–mediated clearance: studies in vitro and in vivo[J]. Clinical pharmacology & therapeutics, 2005, 77(1): 63-75.
[7] Blount MA, Beasley A, Zoraghi R, et al. Binding of tritiated sildenafil, tadalafil, or vardenafil to the phosphodiesterase-5 catalytic site displays potency, specificity, heterogeneity, and cGMP stimulation. Mol Pharmacol. 2004;66(1):144-152.
[8] Salloum F N, Chau V Q, Hoke N N, et al. Tadalafil prevents acute heart failure with reduced ejection fraction in mice[J]. Cardiovascular drugs and therapy, 2014, 28(6): 493-500.
Tadalafil是一种有效、可逆且具有选择性的磷酸二酯酶5（PDE5）小分子抑制剂，IC50为1.8nM。Tadalafil还能够抑制PDE11（IC50为11nM）[1-2]。PDE是调节细胞内环核苷酸周转和平滑肌张力的关键蛋白质 [3]。Tadalafil可用于治疗勃起功能障碍和改善肺动脉高压 [4]。
在体外，不同浓度的Tadalafil（0.2、0.1、0.05和0.025μg/ml; 0.5ml; 2h）处理人正常精子组和弱精子组收集的精液样品，在0.025μg/ml浓度下精子活力显著增加 [5]。Tadalafil（1、3和10μM; 48h）增加了在人肝细胞中CYP3A蛋白的表达，而CYP3A活性没有相应增加 [6]。
在体内，Tadalafil（0.09mg/200g weight/d; gavage; 2 months）显著改善链脲佐菌素诱导的糖尿病大鼠的勃起功能，增加了平滑肌和弹性组织的面积百分比，并显著减少纤维组织 [7]。Tadalafil（1mg/kg/day; 4 weeks; i.p.）治疗减轻了心肌梗死（MI）小鼠的心脏肥大和肺水肿，减少了纤维化面积以及细胞凋亡 [8]。