Phosphodiesterase-5 (PDE5) is a homodimer that belongs to mammalian PDE family. The catalytic domain of PDE5 catalyzes the breakdown of cGMP to 5’-GMP. Tadalafil is a PDE5 inhibitor with an IC50 value of 1.8 0.4nM. The stoichiometry of [3H]Tadalafil binding to PDE5 was 0.68 0.10 mol/subunit. The KD (isotherm), KD (dissociation rate), and KD (1/2 EC50) values of tadalafil against PDE5 were 2.4 0.60, 1.9 0.37, and 2.7 0.25nM, respectively[5]. Tadalafil also inhibits human cytochrome P450 (CYPs) with Ki values of 41 5, 66 6, 73 8, and 14 1μM against CYP3A-, CYP2C9-, CYP2C19-, and CYP1A2-mediated metabolism, respectively. Tadalafil at the dose of 1μM or greater induced the protein level of CYP3A in hepatocytes. The CYP3A activity was increased by 1μM tadalafil, but this induction was suppressed after the exposure to 10μM tadalafil. Also in hepatocyte cultures, the exposure to 0.1 – 1μM tadalafil slightly inhibited CYP3A-mediated midazolam 1’-hydroxylase activity. With the treatment of 10μM tadalafil, 1’-OH-midazolam formation was significantly inhibited in a time-dependent manner[6]. In mice subjected to cavernous nerve resection, treatment with tadalafil (1.3 gm per day) via oral gavage for 20 days decreased the number of apoptotic cells and increased the phosphorylation of the 2 survival associated kinases, Akt and extracellular signal-regulated kinase 1/2[7].
作用机制
Tadalafil inhibits PDE5 by specifically binding to the catalytic site of PDE5[5].
To investigate the effect of Tadalafil on mature GIE, results showed that Tadalafil-treated GIE were cleared faster from the peripheral blood and retained more in the spleen.
Front Cell Infect Microbiol. 2022 May 25;12:883759.
Raw264.7 macrophages
25 µM
48 hours
TA significantly suppressed M2 polarization and promoted M1 polarization
J Immunother Cancer. 2023 Feb;11(2):e006493.
Primary macrophages from mice
25 µM
48 hours
TA significantly suppressed M2 polarization and promoted M1 polarization
J Immunother Cancer. 2023 Feb;11(2):e006493.
MDA-MB-231 cells
50, 100, 150 µM
48 hours
To detect the total protein levels of H4R3me2s and H3R8me2s, the results showed that compounds A, B, C, and Tadalafil reduced the total levels of H4R3me2s and H3R8me2s in the cells in a dose-dependent manner, with compound A having the strongest effect.
Int J Mol Sci. 2022 Apr 27;23(9):4806.
MCF-7 cells
150 µM
48 hours
To detect cell proliferation, the results showed that compound A had the strongest inhibitory effect on MCF-7 cell proliferation at 150 μM.
Int J Mol Sci. 2022 Apr 27;23(9):4806.
HCC1937 cells
150 µM
48 hours
To detect cell proliferation, the results showed that compound A had the strongest inhibitory effect on HCC1937 cell proliferation at 150 μM.
Int J Mol Sci. 2022 Apr 27;23(9):4806.
Tadalafil/他达拉非 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Wistar Albino rats
Alcohol-induced gastric ulcer model
Oral
10 mg/kg
Single dose, lasting 1 hour
To evaluate the gastroprotective effect of Tadalafil against alcohol-induced gastric ulcers, the results showed that Tadalafil significantly reduced the ulcer area and ulcer index.
Int J Nanomedicine. 2020 Dec 14;15:10099-10112
C57/B6 mice
L-NAME-induced preeclampsia and fetal growth restriction model
Oral
13.9 ± 1.9 mg/kg BW/day
From day 14 to day 17 of pregnancy, daily administration
Tadalafil treatment improved neurodevelopment in FGR offspring, reduced the expression of hypoxia marker HIF-2α in the placenta and fetal brain, and improved synaptogenesis and myelination in offspring on P15 and P30.
Sci Rep. 2019 Jan 18;9(1):234
C57BL/6 mice
Orthotopic HCC model
Tail vein injection
2 mg/kg
Not specified
TA reversed the immunosuppressive TME by regulating M2 TAMs and MDSCs
J Immunother Cancer. 2023 Feb;11(2):e006493.
Nude mice
MDA-MB-231 xenograft model
Gastric gavage
2 mg/kg
Once daily for 21 days
To evaluate the effect of compound A on tumor growth, the results showed that compound A alone slowed tumor growth and further enhanced the efficacy of chemotherapeutics when used in combination.
Int J Mol Sci. 2022 Apr 27;23(9):4806.
Rats
Fructose-fed rat model
Gavage
2 mg/kg
Once daily for four weeks
Tadalafil ameliorated chronic ischemia-associated bladder overactivity by promoting pelvic angiogenesis and enhancing p-eNOS expression.
Int J Mol Sci. 2025 Feb 6;26(3):1363
NSG mice
Humanized mouse model
Oral
8 mg/kg
Once daily for 4 days
To investigate the effect of Tadalafil on the circulation of mature GIE in vivo, results showed that Tadalafil treatment significantly reduced the presence of GIE in the circulation and promoted their accumulation in the spleen.
Front Cell Infect Microbiol. 2022 May 25;12:883759.
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