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Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-Week repeated oral administration in rats
- Source :
- Biopharmaceutics & Drug Disposition. 24:409-418
- Publication Year :
- 2003
- Publisher :
- Wiley, 2003.
-
Abstract
- 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 (AUC0−24 h) was significantly different among the three doses (the AUC0–24 h based on 20 mg/kg/day was 2.33, 7.00 and 4.19 μg 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 AUC0–24 h of DA-8164 after dose-normalized to 20 mg/kg/day of DA-8159 were 2.74, 5.00 and 1.68 μg h/ml, respectively. Copyright © 2003 John Wiley & Sons, Ltd.
- Subjects :
- Male
medicine.medical_specialty
No-observed-adverse-effect level
Phosphodiesterase Inhibitors
Metabolite
Administration, Oral
Pharmaceutical Science
Spleen
Pharmacology
Drug Administration Schedule
Rats, Sprague-Dawley
chemistry.chemical_compound
Oral administration
Internal medicine
Blood plasma
medicine
Animals
Toxicokinetics
Pharmacology (medical)
Chromatography, High Pressure Liquid
No-Observed-Adverse-Effect Level
Sulfonamides
business.industry
Body Weight
Organ Size
General Medicine
Rats
Pyrimidines
medicine.anatomical_structure
Endocrinology
chemistry
Area Under Curve
Toxicity
Female
Bone marrow
business
Subjects
Details
- ISSN :
- 1099081X and 01422782
- Volume :
- 24
- Database :
- OpenAIRE
- Journal :
- Biopharmaceutics & Drug Disposition
- Accession number :
- edsair.doi.dedup.....5f9558eeada87028287958f9630b6289