Pharmacokinetics and tissue distribution of a novel PDE5 inhibitor, SK-3530, in rats

Abstract

Aim: To investigate the pharmacokinetic profile and tissue distribution of a novel phosphodiesterase type 5 inhibitor, 5-ethyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-2-propoxy-phenyl}-7-propyl-3,5-dihydro-pyrrolo(3,2-d)pyrimidin-4-one (SK-3530), in rats after administration of the The maximum plasma concentration and area under the curve of the parent SK3530 were 10%-20% compared to those of the total radioactivity. After the oral administration of [ 14 C]SK-3530, the radioactivity was widely distributed in all tissues, and the tissue/plasma ratio of the radioactivity 1 h after administration was calculated as 0.5-2.6 with the exception of excretory organs. A relatively high penetration was shown in the adrenal glands, liver, and lung. In vitro and ex vivo plasma protein binding assay by ultrafiltration showed a considerably high binding rate of more than 97%. Conclusion: SK-3530 was relatively well absorbed in the gastrointestinal tract and showed linear pharmacokinetics over the investigated dose range. SK-3530 had low oral bioavailability due to a high, first-pass metabolism.

The Penile Erection Efficacy of a New Phosphodiesterase Type 5 Inhibitor, Mirodenafil (SK3530), in Rabbits with Acute Spinal Cord Injury

“…These modifications confer a more potent and selective inhibitory effect on PDE5 to mirodenafil than those of sildenafil [26]. Pharmacokinetic data for mirodenafil suggests that it is relatively well absorbed in the gastrointestinal tract and shows linear pharmacokinetics over the investigated dose range [32]. Based on unpublished data, mirodenafil for which is currently under phase III clinical investigation, appears to be safe and effective for treatment of male ED [25,26,32].…”

Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis

“…This physiological response is mediated by the neurotransmitter nitric oxide (NO) that is released from both nitrergic nerves and sinusoidal endothelium. Nitric oxide stimulates the soluble guanylyl cyclase in cavernosal smooth muscle, inducing increased synthesis of cyclic GMP (cGMP) to lead relaxation of smooth muscle [2] . The cGMP levels in the corpus cavernosum are regulated by soluble guanylyl cyclase and cyclic nucleotide phosphodiesterases (PDEs).…”

Mirodenafil for the Treatment of Erectile Dysfunction: A Systematic Review of the Literature

“…The corpus cavernosum concentration reached a C max of 2,812 ng/mL at 1.4 hours after dosing in rats and decreased with a t 1/2 of 1.3 hours. After oral administration of mirodenafil (100 mg) in humans, the C max was 354.9 ng/mL at 1.0 hour and decreased with a t 1/2 of 1.6 hours [5,6,7]. …”

“…Oral bioavailabilities based on total radioactivity are estimated to be 60.4%, 62.2%, and 69.9% for 10, 20, and 40 mg/kg doses in rats, respectively. The oral bioavailabilities of parent mirodenafil have been estimated to be 24.1%, 30.1%, and 43.4% for 10, 20, and 40 mg/kg doses in rats, respectively [5], which resulted from extensive first-pass metabolism. After oral administration of mirodenafil (20 mg/kg), ~2.59% of the oral dose is not absorbed, and the hepatic and gastrointestinal first-pass effects of mirodenafil are ~21.4% and ~54.3% of the oral dose, respectively [8].…”