Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-week repeated oral administration in rats.
The subacute toxicities (10 male and 10 female rats at each dose) and the toxicokinetics (5 male rats at each dose) of DA-8159, a new phosphodiesterase type V (PDE V) inhibitor, were evaluated after single (at day 1) and 4-week (at day 28) oral administration of the drug at doses of 0 (to serve as a control), 20, 80 and 320 mg/kg/day to rats. DA-8159 showed a decrease in body weight gain, clinical signs such as chromodacryohaemorrhoea, ptosis and decreased locomotor activity, an increase in WBC number, changes in parameters related to RBCs, an increase in organ weight of the liver, spleen and lung, and finally microscopic lesions such as cholangiofibrosis and inflammatory cell infiltration in the liver, alveolar macrophage accumulation, and inflammatory cell infiltration in the lung, an increase in bone marrow density and extrahaematopoiesis in the spleen. These changes were observed mainly at a dose of 80 mg/kg or above. While some changes were observed at a dose of 20 mg/kg, these changes were non-specific and transient since this were also observed in control rats. In addition, there was no dose-dependency in these changes. Based on these results, the NOAEL (No-Observed-Adverse-Effect-Level) for DA-8159 in rats was estimated to be 20 mg/kg/day, and the target organs were determined to be liver, bone marrow, spleen, lung and blood cells. After a 4-week oral administration, accumulation of DA-8159 was evident at a dose of 20 mg/kg/day, but was not considerable at toxic doses (80 and 320 mg/kg/day). After a single oral administration, the dose-normalized area under the plasma concentration-time curve from time zero to the last measured time, 24 h, in plasma (AUC(0-24 h)) was significantly different among the three doses (the AUC(0-24 h) based on 20 mg/kg/day was 2.33, 7.00 and 4.19 microg h/ml for 20, 80 and 320 mg/kg/day, respectively). Similar results were also obtained from DA-8164, a metabolite of DA-8159; the AUC(0-24 h) of DA-8164 after dose-normalized to 20 mg/kg/day of DA-8159 were 2.74, 5.00 and 1.68 microg h/ml, respectively.
Shim
Hyun J
HJ
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea.
Kim
Yu C
YC
Jang
Ji M
JM
Park
Kyung J
KJ
Kim
Dong H
DH
Kang
Kyung K
KK
Ahn
Byoung O
BO
Kwon
Jong W
JW
Kim
Won B
WB
Lee
Myung G
MG
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D000096926:Benzenesulfonamides
D010726:Phosphodiesterase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; C419664:udenafil; D000096926:Benzenesulfonamides