title: DA-8159 has erectile potentials much longer than the plasma half-life in a conscious rabbit model.
abstract: DA-8159 is a pyrazolopyrimidinone derivative which is a potent and selective phosphodiesterase type 5 inhibitor. The efficacy of oral DA-8159 has been demonstrated in conscious and spinalized rabbits by its enhancement of nitric oxide-induced erections. The aim of this study was to investigate the time dependency of this efficacy on its plasma concentration in rabbits. DA-8159 was given orally to normal rabbits at a dose of 10 or 30 mg/kg in order to determine its pharmacokinetic parameters. After then, to investigate the relationship between penile erectile activity and plasma half-life, a dose of 10 mg/kg DA-8159 was administered and the erectile response was examined in a time-course manner by measuring the length of the uncovered penile mucosa after the intravenous administration of sodium nitroprusside, which was administered 1, 3, 6, 8, 24 hours after administering DA-8159. DA-8159 was absorbed rapidly with a Tmax of 0.6 hours in 30 mg/kg and 1.0 hour in the 10 mg/kg group, and T1/2 of 1.23 hours in 30 mg/kg and 1.17 hours in 10 mg/kg, respectively. DA-8159 was not detected in the blood plasma 3 hours (10 mg/kg) or 6 hours (30 mg/kg) after administration. In an erection test, DA-8159 alone (10 mg/kg) induced a penile erection for approximately 2 hours but there was no significant erection thereafter. Although the DA-8159-induced penile erection disappeared, an intravenous injection of sodium nitroprusside significantly induced a penile erection for 6 hours, when the plasma drug concentration was below the detection limit and a no longer visible erection was noted. These results demonstrate that DA-8159 is absorbed and rapidly cleared in rabbits. In addition, it can enhance a sodium nitroprusside-induced penile erection even after 6 hours, which is approximately five times longer than the plasma half-life in the rabbits. These results suggest that DA-8159 may have an erectile potential for much longer than its measured half-life.
authors.affiliation: Research Laboratories of Dong-A Pharmaceutical Company, 47-5, Sanggal, Kiheung, Yongin, Kyunggi 449-900, South Korea. kangkk@empal.com
authors.forename: Kyung Koo
authors.initials: KK
authors.lastname: Kang
authors.forename: Gook Jun
authors.initials: GJ
authors.lastname: Ahn
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Shim
authors.forename: Jong Won
authors.initials: JW
authors.lastname: Kwon
mesh_terms: D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007172:Erectile Dysfunction / Q000188:drug therapy*; D006207:Half-Life; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010410:Penile Erection / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D013449:Sulfonamides; D013997:Time Factors; D000096926:Benzenesulfonamides
chemical_list: D009599:Nitroprusside; D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C419664:udenafil; D000096926:Benzenesulfonamides