Subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, after single and 4-week repeated oral administration in dogs.

The subacute toxicities and toxicokinetics of a new erectogenic, DA-8159, were evaluated after single (at the 1st day) and 4-week (at the 28th day) oral administration of the drug, in doses of 0 (to serve as a control), 12.5, 50 and 200 mg/kg/day, to male and female dogs (n=3 for male and female dogs for each dose). DA-8159 had an effect on the immune-related organs (or tissues), circulatory systems, liver, adrenal glands, ovaries and pancreas. The toxic dose was 200 mg/kg and no observed adverse effect level was less than 50 mg/kg for male and female dogs. There were no significant gender differences in the pharmacokinetic parameters of DA-8159 for each dose after both single and 4-week oral administration. The pharmacokinetic parameters of DA-8159 were dose-independent after single oral administration; the time to reach a peak plasma concentration (T(max)) and the dose-normalized area under the plasma concentration-time curve from time zero to 24 h in plasma (AUC(0-24 h)) were not significantly different among three doses. However, accumulation of DA-8159 after 4-week oral administration was considerable at toxic dose, 200 mg/kg/day. For example, after 4-week administration, the dose-normalized AUC(0-24 h) value at 200 mg/kg/day (4.71 and 15.3 microg h/ml) was significantly greater than that at 12.5 mg/kg/day. After 4-week oral administration, the dose-normalized C(max) and AUC(0-24 h) at 200 mg/kg/day were significantly higher and greater, respectively, than those after a single oral administration.