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].
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