Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum

Haroldo Alfredo Flores Toque, Cleber E. Teixeira, Raquel Lorenzetti, Cristina E. Okuyama, Edson Antunes, Gilberto De Nucci

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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 μM) phenylephrine-precontracted rabbit and human corpus cavernosum. The cavernosal relaxations evoked by either acetylcholine (0.01-100 μM) 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.

Original languageEnglish (US)
Pages (from-to)189-195
Number of pages7
JournalEuropean Journal of Pharmacology
Volume591
Issue number1-3
DOIs
StatePublished - Sep 4 2008
Externally publishedYes

Fingerprint

Phosphodiesterase 5 Inhibitors
Pharmacology
Rabbits
Oral Administration
Nitric Oxide
Nitrergic Neurons
Pharmacokinetics
Penile Erection
lodenafil carbonate
Prodrugs
Phenylephrine
Tandem Mass Spectrometry
Complex Mixtures
Baths
Liquid Chromatography
Intravenous Administration
Electric Stimulation
Acetylcholine
Hydrolysis
Blood Platelets

Keywords

  • Cyclic GMP
  • Dimerization
  • Erectile dysfunction
  • Nitric oxide
  • Pro-drug
  • Sildenafil

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. / Flores Toque, Haroldo Alfredo; Teixeira, Cleber E.; Lorenzetti, Raquel; Okuyama, Cristina E.; Antunes, Edson; De Nucci, Gilberto.

In: European Journal of Pharmacology, Vol. 591, No. 1-3, 04.09.2008, p. 189-195.

Research output: Contribution to journalArticle

Flores Toque, Haroldo Alfredo ; Teixeira, Cleber E. ; Lorenzetti, Raquel ; Okuyama, Cristina E. ; Antunes, Edson ; De Nucci, Gilberto. / Pharmacological characterization of a novel phosphodiesterase type 5 (PDE5) inhibitor lodenafil carbonate on human and rabbit corpus cavernosum. In: European Journal of Pharmacology. 2008 ; Vol. 591, No. 1-3. pp. 189-195.
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